Films and methods of manufacture

ABSTRACT

Embodiments of the present disclosure are directed to perforated polymer films and methods of making the same. In some embodiments, the films are for use with implantable medical devices. In one embodiment there is a flexible body including a polymer film having a first surface and an opposing second surface, the film having a plurality of apertures extending from the first surface to the second surface and a plurality of raised lips protruding from the first surface such that each of the plurality of apertures is surrounded by a one of the plurality of raised lips. In one embodiment, the film comprises a single layer, and in another embodiment, the film can comprise a plurality of layers. In certain embodiments, the film can comprise an adhesive layer. In another embodiment, one or more of the layers may be a drug containing layer and/or a rate controlling layer for drug release.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 61/837,716, filed Jun. 21, 2013, titled “Films andMethods of Manufacture,” which is hereby incorporated by reference inits entirety.

INCORPORATIONS BY REFERENCE

U.S. patent application Ser. No. 12/089,574, filed on Apr. 8, 2008, is anational stage application of PCT/US2006/040038, filed Oct. 12, 2006,and both applications are hereby incorporated by reference in theirentirety. U.S. patent application Ser. No. 13/727,682, filed on Dec. 27,2012, claims the benefit of U.S. Provisional Patent Application No.61/580,679 filed Dec. 28, 2011 entitled “Films and Methods ofManufacture,” and both applications are hereby incorporated by referencein their entirety.

FIELD OF THE DISCLOSURE

The present disclosure generally relates to films (e.g., polymer films)and methods of manufacture, and in at least some embodiments, perforatedfilms and methods of medical use.

BACKGROUND

High-energy lower extremity fractures have been associated with surgicalsite infection (SSI) and osteomyelitis rates ranging from approximately14% to 60% in both military and civilian settings. The current standardfor treatment of such fractures typically includes using metal implants(plates and screws or nails) for fracture fixation, which have thepotential disadvantage of placing metal within a fracture site. Thesemetal implants can serve as sites for bacterial adhesion and formationof a bacterial biofilm, where bacteria can remain sequestered from thebody's immune system, resulting in surgical site infections.

Although the use of intravenous (IV) antibiotics as a prophylaxisagainst wound infection has become standard, infection rates in certaintypes of orthopedic trauma remain high. Systemic antibiotics may notreach the implant surface in sufficient concentration due to locallyimpaired circulation at the wound site, and bacterial biofilm formationcan be very rapid. Biofilm based infections are not only resistant tosystemic antibiotic therapy and the host immune system, they typicallyrequire additional surgery to remove the infected implant.

Locally delivered antibiotics hold promise for reducing SSIs,particularly those associated with high-energy fractures, as they can beused to deliver high concentrations of antibiotics where needed andprevent the development of biofilms on the implant surface. Multiplestudies in animals have demonstrated that if an implant surface can beprotected from colonization by bacteria for a period of time immediatelyafter surgery, the rate of subsequent infection can be significantlyreduced.

Surgeons have used a variety of products for local delivery ofantibiotics, typically aminoglycosides and/or vancomycin, includingpolymethyl methacrylate (PMMA) cements, beads, gels, and collagensponges. However, in certain situations, these antibiotic treatments arenot practical, for example where they take up space at the site makingwound closure difficult, and in other situations may also require aseparate surgery for their removal.

Infections represent a major challenge in orthopedic or trauma surgery.Despite prophylactic measures like asepsis and antisepsis, the surgerysite is still a site of access for local pathogens to become virulentand cause infections.

Coating an implantable device with a drug, such as an antibiotic, hasbeen effective to reduce infection. However, given the large number,sizes, and shapes of implants and other medical devices, the regulatory,financial, and logistical burden of providing a coating for each deviceis enormous. The problem is amplified if one considers additional drugsto use in coatings such as analgesics, antineoplastic agents and growthpromoting substances.

SUMMARY

Embodiments of the present disclosure are directed to polymer films, andin some embodiments, perforated polymer films and novel casting methodsof making the same. In some embodiments, the films are for use withimplantable medical devices though the films may be used in anyapplication.

Commercial methods of forming a perforated film currently existinggenerally involve forming a solid film as a first step, then punching orcutting holes into the film as a second step. An advantage of at leastsome of the embodiments described herein is that the holes or aperturesof the film are formed at the same time that the film is formed. Thismay be useful when the polymer film to be formed is very thin and atrisk for damage due to subsequent handling or processing or when thethickness and/or strength of the film makes it difficult to punch or cutby traditional methods without damaging the film. Such a process mayalso be advantageous when the polymer solution contains an active agentthat may be damaged by subsequent hole-punching steps. The active agentmay be a drug, such as an anti-microbial agent, including one or more ofan anti-bacterial agent, an anti-viral agent, and anti-parasitic agentof the type known to one having ordinary skill in the art, or anysuitable alternative active agent, such as an anti-inflammatory, asteroid, an analgesic, an opioid, a growth factor, or the like,

Embodiments of the present disclosure may also be useful for makingquantities of cast film such as those which are considered too small tomake economically by traditional methods which are typically continuousprocesses designed for high volume production. An additional advantageof at least some embodiments of the present disclosure is that apertures(or perforations) formed in the cast sheet can have complex shapes. Afurther advantage of certain embodiments of the disclosure is that atleast one side of the film may be formed to have a non-planar surfacewhich in some embodiments increases (or reduces) friction and gives animproved tactile feel. These advantages of the present disclosure, aswell as others, are described in further detail below.

In one embodiment there is a flexible body comprising a film (e.g., apolymer film) having a first surface and an opposing second surface, thefilm having a plurality of apertures extending from the first surface tothe second surface and a plurality of raised lips protruding from thefirst surface such that each of the plurality of apertures is surroundedby a one of the plurality of raised lips. In a preferred embodiment, thefilm is comprised of a polymeric material (i.e., a polymer film). In oneembodiment, the film comprises a single layer, and in anotherembodiment, the film can comprise a plurality of layers, for example,two or more layers, such as two layers, three layers, four layers, up toand including seven layers. In certain embodiments, the film cancomprise an adhesive layer, for example, the first surface or the secondsurface of the film, or both, can comprise an adhesive layer. In anotherembodiment, one or more of the layers may be a drug containing layerand/or a rate controlling layer for drug release (with or without a drugcontained therein).

In one embodiment, the polymer material comprises a bioresorbablepolymer. In one embodiment, the bioresorbable polymer comprises apolyester or blend of polyesters (collectively “polyesters”) and theirco-polymers and derivatives. In certain preferred embodiments thepolyester(s) is hydrolyzable. Suitable polyesters can include, forexample, polyglycolic acid, polylactic acid and polycaprolactone. In oneembodiment, the bioresorbable polymer is a copolymer of glycolide,trimethylene carbonate, lactide and caprolactone.

In one embodiment, the first surface includes a contiguous planarportion extending between the plurality of raised protruding lips. Inone embodiment, the plurality of raised protruding lips each have anouter edge that is raised above the contiguous planar portion byapproximately 0.1 mm to approximately 1.0 mm. In one embodiment, thepolymer film comprises a plurality of discrete eluting drug componentsand wherein the polymer film is configured to elute the plurality ofdiscrete drug components at different time periods followingimplantation of the flexible body. In a further embodiment, the flexiblebody comprises at least one attachment configured to form the polymerfilm into a sleeve. In one embodiment, the polymer film has a firsttensile strength in a first planar direction and a second tensilestrength in a second planar direction that is perpendicular to the firstplanar direction, wherein the first tensile strength is substantiallyequal to the second tensile strength. In one embodiment, the polymerfilm has a nominal thickness of no greater than 0.06 mm. In oneembodiment, the first surface has a first tactile feel that is differentfrom a second tactile feel of the second surface.

In another embodiment there is a method of producing a polymer filmcomprising: placing a polymer solution into a one sided mold having aplurality of protrusions extending from a bottom of the mold. In certainembodiments, the polymer solution is characterized by a viscosity thatinhibits the unaided flow of the polymer throughout the mold. Theprocess further includes urging the polymer solution around each of theplurality of protrusions; and solidifying the polymer solution. In oneembodiment, the mold includes a perimeter form extending to an elevationthat is substantially equal to an elevation of each of the plurality ofprotrusions. In one embodiment, the urging comprises drawing an urginginstrument such as a blade, bar, squeegee or roller across the perimeterform and the plurality of protrusions to force the polymer solution toflow around the plurality of protrusions and throughout the mold suchthat the polymer solution has a substantially uniform thickness. In oneembodiment, at least a portion of an outer surface of a protrusion, forexample an upper portion of a protrusion, is substantially free ofpolymer solution after the drawing. In one embodiment, the placing stepincludes depositing the polymer solution in the mold such that a portionof the polymer solution is above the elevation of the perimeter form andthe protrusions. In a still further embodiment, one or more of themethod steps can be repeated such that a film comprising a plurality oflayers may be produced, for example, two or more layers, such as twolayers, three layers, four layers, up to and including seven layers. Incertain embodiments, the method additionally includes the steps ofplacing one or more additional polymer solutions in the mold over afirst polymer solution, and urging the one or more polymer solutionsaround each of the plurality of protrusions. These steps can occur priorto, during, or after the step of solidifying the polymer solution. Thus,according to one embodiment of the method, each of the one or morepolymer solutions placed in the mold can solidify prior to, during, orafter, the step of placing the next or subsequent additional polymersolution into the mold. According to one embodiment, the one or morepolymer solutions comprises a polymer solution that can solidify into anadhesive layer, and according to another embodiment, the one or morepolymer solutions comprises a rate controlling layer for drug release.

In one embodiment, solidifying the polymer solution includes reducing athickness of the polymer solution. In one embodiment, solidifying thepolymer solution includes forming a meniscus of solidified polymeraround each of the plurality of protrusions. In one embodiment, distancefrom the bottom of the mold to a top of each of the plurality ofprotrusions is less than approximately 0.3 mm. In one embodiment, thepolymer solution contains a drug. In one embodiment, the polymersolution is formed by combining a solvent, a polymer, and the drug at atemperature below 90° C. In one embodiment, the perimeter form defines atotal mold area and the plurality of protrusions defines an area that isat least about 15% of the total mold area. In a further embodiment, themethod comprises peeling, or otherwise removing, the drug eluting filmfrom the mold.

In one embodiment, the polymer solution comprises a cross-linkablepre-polymer solution. In one embodiment, the solidifying step includescross-linking the polymer by applying UV radiation, temperature change,polymerization catalysts, soluble crosslinking agents or combinationsthereof to the polymer solution. In one embodiment, the polymer solutionincludes discrete drug units. In one embodiment, the polymer solutioncomprises a first solvent and a polymer and the solidifying stepincludes exposing the polymer solution to a second solvent in which thefirst solvent is soluble and in which the polymer and the drug are notsoluble such that the first solvent is at least substantially removedfrom the polymer solution and the polymer solidifies to contain thedrug.

The polymer films disclosed herein may be used to inhibit microbialinfection at a surgical site, including bacterial colonization of amedical implant implanted at the surgical site. Typically, the methodscomprise identifying a surgical site in need of microbial inhibition andcontacting the surgical site with a polymer film comprising an activeagent (e.g., drug). The methods may also involve identifying a zone at asurgical site or on a medical implant needing microbial inhibition,contacting the medical implant with the polymer film, e.g., by affixingthe polymer film to the implant, and implanting the medical implant atthe surgical site. Because the contacting of the polymer film and themedical implant are done at or near the time of surgery, i.e.,intraoperatively, the surgeon can match the polymer film with themedical implant to be contacted based on the size and shape of themedical implant and the drug requirements for the subject patient.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofembodiments of the polymer films and methods of manufacture, will bebetter understood when read in conjunction with the appended drawings ofexemplary embodiments. It should be understood, however, that theinvention is not limited to the precise arrangements andinstrumentalities shown.

In the drawings:

FIG. 1A is an enlarged perspective schematic view of a portion of a film(in this instance a polymer film) in accordance with an exemplaryembodiment of the present disclosure;

FIG. 1B is a 60× magnified photo of an aperture of a polymer film inaccordance with an exemplary embodiment of the present disclosure;

FIG. 2 is a top view of three exemplary sleeves formed from the polymerfilm of FIG. 1B in combination with a respective implantable medicaldevice;

FIG. 3A is a perspective view of a portion of a mold in accordance withan exemplary embodiment of the present disclosure;

FIG. 3B is a top plan view of the mold of FIG. 3A;

FIG. 3C is a cross-sectional side view of the mold of FIG. 3B takenabout line C-C in FIG. 3B;

FIG. 3D is an enlarged corner section of the mold shown in FIG. 3B;

FIG. 3E is an enlarged cross section of the mold shown in FIG. 3D takenalong line 3E-3E;

FIG. 3F is an enlarged perspective photograph of a section of the moldof FIG. 3A;

FIG. 3G is an enlarged perspective photograph of a section of the moldin accordance with another exemplary embodiment of the presentdisclosure;

FIG. 4A is a schematic side cross-sectional view of the mold of FIG. 3Awith the polymer added;

FIG. 4B is a schematic side cross-sectional view of the mold shown inFIG. 4A showing the drawing device drawing the polymer across the mold;

FIG. 4C is a schematic side cross-sectional view of the mold shown inFIG. 4A showing the polymer after being drawn across the mold andsolidified to form a polymer film;

FIG. 4D is a schematic side cross-sectional view of the mold shown inFIG. 4C showing the polymer after being drawn across the mold andsolidified to form a polymer film in accordance with another embodiment;

FIG. 4E is a schematic side cross-sectional view of the mold shown inFIG. 4C showing the polymer after being drawn across the mold andsolidified to form a polymer film in accordance with yet anotherembodiment;

FIG. 5 is a perspective view of an automated casting apparatus inaccordance with an exemplary embodiment of the present disclosure;

FIG. 6 is a perspective view of the automated casting apparatus of FIG.5 showing the polymer being added to the mold;

FIG. 7 is a perspective view of the automated casting apparatus of FIG.5 showing the drawing device drawing the polymer across the mold;

FIG. 8 is a perspective view of polymer being added to a mold inaccordance with another exemplary embodiment of the present disclosure;

FIG. 9 is a perspective view of the mold of FIG. 8 showing the drawingdevice drawing the polymer across the mold;

FIG. 10 is a perspective view of the mold of FIG. 8 showing the polymerfilm being removed from the mold;

FIG. 11A is a top plan view of a sleeve that comprises at least onepolymer film of the type illustrated in FIG. 1 shown in oneconfiguration;

FIG. 11B is a top plan view of a sleeve that comprises at least onepolymer film of the type illustrated in FIG. 1 shown in anotherconfiguration;

FIG. 11C is a top plan view of a sleeve that comprises at least onepolymer film of the type illustrated in FIG. 1, shown in anotherconfiguration;

FIG. 11D is a top plan view of a sleeve that comprises at least onepolymer film of the type illustrated in FIG. 1, shown in anotherconfiguration;

FIG. 11E is a top plan view of a sleeve that comprises at least onepolymer film of the type illustrated in FIG. 1, shown in anotherconfiguration;

FIG. 11F is a top plan view of a sleeve that comprises at least onepolymer film of the type illustrated in FIG. 1, shown in anotherconfiguration;

FIG. 11G is a top plan view of a sleeve that comprises at least onepolymer film of the type illustrated in FIG. 1, shown in anotherconfiguration;

FIG. 11H is a top plan view of a sleeve that comprises at least onepolymer film of the type illustrated in FIG. 1, shown in anotherconfiguration;

FIG. 11I is a top plan view of a sleeve that comprises at least onepolymer film of the type illustrated in FIG. 1, shown in anotherconfiguration;

FIG. 11J is a top plan view of a sleeve that comprises at least onepolymer film of the type illustrated in FIG. 1, shown in anotherconfiguration;

FIG. 11K is an enlarged perspective view of a portion of the film ofeach of the sleeves as illustrated in FIGS. 11A-J in accordance with oneembodiment;

FIG. 11L is an enlarged top plan view of a portion of each of thesleeves as illustrated in FIGS. 11A-J, such as a top plan view of thearea within region 11E in FIG. 11E;

FIG. 11M is an enlarged view of a seam of a sleeve such as those shownin FIGS. 11A-11J;

FIG. 12 is a yield stress graph of a polymer film in accordance with anexemplary embodiment of the present disclosure;

FIG. 13 is a strain at yield graph of a polymer film in accordance withan exemplary embodiment of the present disclosure;

FIG. 14 is a graph illustrating the rate of drug release over time whena sleeve in accordance with an exemplary embodiment of the presentdisclosure is placed into saline solution;

FIG. 15 is an in-vitro mass loss graph of a polymer film in accordancewith an exemplary embodiment of the present disclosure;

FIG. 16 is an in-vitro molecular weight loss graph of a polymer film inaccordance with an exemplary embodiment of the present disclosure;

FIG. 17A is a top, front, right perspective view of the sleeveillustrated in FIG. 11A, including a pair of films shown in a closedconfiguration;

FIG. 17B is a sectional elevation view of a portion of the sleeveillustrated in FIG. 17A taken at line 17B-17B of FIG. 17A, showing thesleeve in an open configuration whereby the films are partiallyseparated from each other;

FIG. 17C is a top plan view of the sleeve illustrated in FIG. 17A;

FIG. 17D is a bottom plan view of the sleeve illustrated in FIG. 17A;

FIG. 17E is a rear elevation view of the sleeve illustrated in FIG. 17A;

FIG. 17F is a front elevation view of the sleeve illustrated in FIG.17A;

FIG. 17G is a right side elevation view of the sleeve illustrated inFIG. 17A;

FIG. 17H is a left side elevation view of the sleeve illustrated in FIG.17A;

FIG. 18A is a top, front, right perspective view of the sleeveillustrated in FIG. 11B, including a pair of films shown in a closedconfiguration;

FIG. 18B is a sectional elevation view of a portion of the sleeveillustrated in FIG. 18A taken at line 18B-18B of FIG. 18A, showing thesleeve in an open configuration whereby the films are partiallyseparated from each other;

FIG. 18C is a top plan view of the sleeve illustrated in FIG. 18A;

FIG. 18D is a bottom plan view of the sleeve illustrated in FIG. 18A;

FIG. 18E is a rear elevation view of the sleeve illustrated in FIG. 18A;

FIG. 18F is a front elevation view of the sleeve illustrated in FIG.18A;

FIG. 18G is a right side elevation view of the sleeve illustrated inFIG. 18A;

FIG. 18H is a left side elevation view of the sleeve illustrated in FIG.18A;

FIG. 19A is a top, front, right perspective view of the sleeveillustrated in FIG. 11C, including a pair of films shown in a closedconfiguration;

FIG. 19B is a sectional elevation view of a portion of the sleeveillustrated in FIG. 19A taken at line 19B-19B of FIG. 19A, showing thesleeve in an open configuration whereby the films are partiallyseparated from each other;

FIG. 19C is a top plan view of the sleeve illustrated in FIG. 19A;

FIG. 19D is a bottom plan view of the sleeve illustrated in FIG. 19A;

FIG. 19E is a rear elevation view of the sleeve illustrated in FIG. 19A;

FIG. 19F is a front elevation view of the sleeve illustrated in FIG.19A;

FIG. 19G is a right side elevation view of the sleeve illustrated inFIG. 19A;

FIG. 19H is a left side elevation view of the sleeve illustrated in FIG.19A;

FIG. 20A is a top, front, right perspective view of the sleeveillustrated in FIG. 11D, including a pair of films shown in a closedconfiguration;

FIG. 20B is a sectional elevation view of a portion of the sleeveillustrated in FIG. 20A taken at line 20B-20B of FIG. 20A, showing thesleeve in an open configuration whereby the films are partiallyseparated from each other;

FIG. 20C is a top plan view of the sleeve illustrated in FIG. 20A;

FIG. 20D is a bottom plan view of the sleeve illustrated in FIG. 20A;

FIG. 20E is a rear elevation view of the sleeve illustrated in FIG. 20A;

FIG. 20F is a front elevation view of the sleeve illustrated in FIG.20A;

FIG. 20G is a right side elevation view of the sleeve illustrated inFIG. 20A;

FIG. 20H is a left side elevation view of the sleeve illustrated in FIG.20A;

FIG. 21A is a top, front, right perspective view of the sleeveillustrated in FIG. 11E, including a pair of films shown in a closedconfiguration;

FIG. 21B is a sectional elevation view of a portion of the sleeveillustrated in FIG. 21A taken at line 21B-21B of FIG. 21A, showing thesleeve in an open configuration whereby the films are partiallyseparated from each other;

FIG. 21C is a top plan view of the sleeve illustrated in FIG. 21A;

FIG. 21D is a bottom plan view of the sleeve illustrated in FIG. 21A;

FIG. 21E is a rear elevation view of the sleeve illustrated in FIG. 21A;

FIG. 21F is a front elevation view of the sleeve illustrated in FIG.21A;

FIG. 21G is a right side elevation view of the sleeve illustrated inFIG. 21A;

FIG. 21H is a left side elevation view of the sleeve illustrated in FIG.21A;

FIG. 22A is a top, front, right perspective view of the sleeveillustrated in FIG. 11F, including a pair of films shown in a closedconfiguration;

FIG. 22B is a sectional elevation view of a portion of the sleeveillustrated in FIG. 22A taken at line 22B-22B of FIG. 22A, showing thesleeve in an open configuration whereby the films are partiallyseparated from each other;

FIG. 22C is a top plan view of the sleeve illustrated in FIG. 22A;

FIG. 22D is a bottom plan view of the sleeve illustrated in FIG. 22A;

FIG. 22E is a rear elevation view of the sleeve illustrated in FIG. 22A;

FIG. 22F is a front elevation view of the sleeve illustrated in FIG.22A;

FIG. 22G is a right side elevation view of the sleeve illustrated inFIG. 22A;

FIG. 22H is a left side elevation view of the sleeve illustrated in FIG.22A;

FIG. 23A is a top, front, right perspective view of the sleeveillustrated in FIG. 11G, including a pair of films shown in a closedconfiguration;

FIG. 23B is a sectional elevation view of a portion of the sleeveillustrated in FIG. 23A taken at line 23B-23B of FIG. 23A, showing thesleeve in an open configuration whereby the films are partiallyseparated from each other;

FIG. 23C is a top plan view of the sleeve illustrated in FIG. 23A;

FIG. 23D is a bottom plan view of the sleeve illustrated in FIG. 23A;

FIG. 23E is a rear elevation view of the sleeve illustrated in FIG. 23A;

FIG. 23F is a front elevation view of the sleeve illustrated in FIG.23A;

FIG. 23G is a right side elevation view of the sleeve illustrated inFIG. 23A;

FIG. 23H is a left side elevation view of the sleeve illustrated in FIG.23A;

FIG. 24A is a top, front, right perspective view of a portion of thesleeve illustrated in FIG. 11H, including a pair of films shown in aclosed configuration;

FIG. 24B is a sectional elevation view of the sleeve illustrated in FIG.23A taken at line 24B-24B of FIG. 24A, showing the sleeve in an openconfiguration whereby the films are partially separated from each other;

FIG. 24C is a top plan view of the sleeve illustrated in FIG. 24A;

FIG. 24D is a bottom plan view of the sleeve illustrated in FIG. 24A;

FIG. 24E is a rear elevation view of the sleeve illustrated in FIG. 24A;

FIG. 24F is a front elevation view of the sleeve illustrated in FIG.24A;

FIG. 24G is a right side elevation view of the sleeve illustrated inFIG. 24A;

FIG. 24H is a left side elevation view of the sleeve illustrated in FIG.24A;

FIG. 25A is a top, front, right perspective view of the sleeveillustrated in FIG. 11I, including a pair of films shown in a closedconfiguration;

FIG. 25B is a sectional elevation view of a portion of the sleeveillustrated in FIG. 25A taken at line 25B-25B of FIG. 25A, showing thesleeve in an open configuration whereby the films are partiallyseparated from each other;

FIG. 25C is a top plan view of the sleeve illustrated in FIG. 25A;

FIG. 25D is a bottom plan view of the sleeve illustrated in FIG. 25A;

FIG. 25E is a rear elevation view of the sleeve illustrated in FIG. 25A;

FIG. 25F is a front elevation view of the sleeve illustrated in FIG.25A;

FIG. 25G is a right side elevation view of the sleeve illustrated inFIG. 25A;

FIG. 25H is a left side elevation view of the sleeve illustrated in FIG.25A;

FIG. 26A is a top, front, right perspective view of the sleeveillustrated in FIG. 11J, including a pair of films shown in a closedconfiguration;

FIG. 26B is a sectional elevation view of a portion of the sleeveillustrated in FIG. 26A taken at line 26B-26B of FIG. 26A, showing thesleeve in an open configuration whereby the films are partiallyseparated from each other;

FIG. 26C is a top plan view of the sleeve illustrated in FIG. 26A;

FIG. 26D is a bottom plan view of the sleeve illustrated in FIG. 26A;

FIG. 26E is a rear elevation view of the sleeve illustrated in FIG. 26A;

FIG. 26F is a front elevation view of the sleeve illustrated in FIG.26A;

FIG. 26G is a right side elevation view of the sleeve illustrated inFIG. 26A; and

FIG. 26H is a left side elevation view of the sleeve illustrated in FIG.26A;

FIG. 27 is graph showing a log reduction in CFUs for a variety ofbacteria in the presence of a drug-containing polymer film according toone embodiment of the present disclosure;

FIG. 28 is a graph showing a minimum effective concentration and zone ofinhibition in the presence of drug-containing polymer films according toembodiments of the present disclosure; and;

FIG. 29 is a graph showing a zone of inhibition against several bacteriain the presence of a drug-containing polymer film according to anembodiment of the present disclosure.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Referring to the drawings in detail, wherein like reference numeralsindicate like elements throughout, there is shown in FIGS. 1A and 3Apolymer films, generally designated 10, and molds, generally designated18, in accordance with exemplary embodiments of the present disclosure.

Referring to the embodiment of FIG. 1A, the film 10 (e.g., a polymerfilm) is a flexible body 11 having a first surface 10 a and a secondsurface 10 b that is opposite the first surface along a transversedirection T. As also illustrated in FIG. 2, the flexible body 11, andthus the film 10, defines first and second opposed sides 10 c and 10 dthat are spaced from each other along a lateral direction A that isperpendicular to the transverse direction T, and first and secondopposed ends 10 e and 10 f that are spaced from each other along alongitudinal direction L that is perpendicular to both the transversedirection T and the lateral direction A. In accordance with oneembodiment, the film 10 is elongate along the longitudinal direction Lso as to define a length along the longitudinal direction L, defines athickness along the transverse direction T, and defines a width alongthe lateral direction A. The sides 10 c and 10 d and the ends 10 e and10 f can define edges, and in combination can define an outer periphery13 of the film 10.

The film may define at least one layer of a biologically compatiblematerial. such as a polymeric material. In one embodiment, the film 10may be formed from a single thin layer of a biologically compatiblematerial. In one embodiment, film 10 is comprised of two or more layersof biologically compatible material, such as two layers, three layers,four layers, up to and including seven layers. In certain embodiments,the film 10 can comprise an adhesive layer. For example, the firstsurface 10 a or the second 10 b surface of the film 10, or both thefirst surface 10 a and the second surface 10 b, can comprise an adhesivelayer, such that the adhesive layer defines one or both of the firstsurface 10 a and the second surface 10 b. For instance, when the film 10is formed from a single layer, the single layer of the film 10 can haveadhesive properties, such that the layer of adhesive is defined by thesingle layer of the film 10 and one or both of the first and secondsurfaces can comprise an adhesive layer. Alternatively, when the film 10comprises a plurality (e.g., at least two) layers, at least one of thetwo or more layers of film 10 can include a layer of adhesive that isapplied to one or both of the first and second surfaces 10 a and 10 b ofthe film. In certain embodiments, one or more of the layers of the film10 may be a drug containing layer and/or a rate controlling layer fordrug release (with or without a drug contained therein). Unlessotherwise indicated, reference herein to one or more layers of the film10 includes both embodiments where the film 10 is formed of a singlelayer, and embodiments where the film comprises a plurality of layers.

In a preferred embodiment, the biologically-compatible material is apolymeric material and in a further preferred embodiment, the polymericmaterial is bioresorbable. In embodiments used with a medical device,such as a bone plate 12 (see FIG. 2), for instance where the film coversat least a portion of the bone plate 12, the film 10, in someembodiments, will dissolve away over time when implanted in vivo and beabsorbed into a patient, leaving only the bone plate 12 behind (such asif bone plate 12 is not also made of a bioresorbable material). The boneplate 12 may also be made of a bioresorbable material in otherembodiments in which case both the bone plate 12 and the film 10 willeventually dissolve. In some embodiments, the film 10 may be configuredto absorb at a different rate from an absorbable bone plate 12 (e.g., afaster or a slower rate). It should be appreciated in certainembodiments that the first surface 10 a of the film 10 can face the boneplate 12 and the second surface 10 b can face away from the bone plate12 during use, and in other embodiments the second surface 10 b of thefilm 10 can face the bone plate 12 and the first surface 10 a can faceaway from the bone plate 12 during use. While reference is made hereinto a bone plate 12, it should be appreciated that the film 10 isconfigured for use in combination with any suitable medical implants asdesired, such as any suitable orthopedic implant used in musculoskeletalrepair, and that unless otherwise indicated herein, reference to a boneplate 12 applies with equal weight to other medical implants.

In some embodiments, a bioresorbable film 10 has advantages overnon-resorbable meshes which, for example, can become encased with orembedded in dense fibrous tissue or present other issues associated withlong term foreign body exposure. In some embodiments, the film 10 isonly partially bioresorbable.

A bioresorbable polymer may be used in order to provide a controlledrelease of a drug such as an antibiotic, with a definite end point.Continuous, long term presence of an antibiotic is often undesirable,since this can create conditions for development of antibiotic resistantbacteria. In one embodiment, complete degradation of the film 10 ensuresthat the drug will be completely released in a pre-determined and/orselectable time. In one embodiment, the drug release can be completelyreleased or substantially completely released even where the film 10 isnot fully absorbed.

The absorption of the film 10 may also impact and/or control the releaseof the antibiotic in the continuous release phase. As the film 10degrades, for example, the permeability of the film may increase, andmore drugs may be released. In some embodiments, the polymer defines afilm that is flexible, has a sufficiently high tensile strength, and canbe processed by solution casting.

One particular class of preferred bioresorbable polymers are thosecontaining aliphatic polyesters. Examples of such polyesters includepolyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL),polydioxanone, poly(trimethylene carbonate) (TMC),polyhydroxyalkanoates, and copolymers, derivatives, and blends of thesame. Bioresorbable polymer materials can differ in their molecularweight, polydispersity, crystallinity, glass transition temperatures,and degradation rates, which can ultimately alter the mechanicalproperties of the film.

Particularly preferred bioresorbable polymers include co-polymercompositions containing PGA, PLA and PCL. According to one embodiment,film 10 is comprised of co-polymer having about 40% to about 95%glycolide content by weight; for example about 60% to about 75%, about60% to about 70%, about 65% to about 75%, and about 68% to about 72%.According to another embodiment, film 10 is comprised of co-polymerhaving about less than 1% (including 0%) to about 50% caprolactonecontent by weight; for example about 5% percent to about 30%, about 10%to about 40%, about 10% to about 22%, about 14% to about 18%, and about30% to about 40%. According to a further embodiment, film 10 iscomprised of about less than 1% (including 0%) to about 15% lactidecontent by weight; for example less than about 1% to about 10%, lessthan about 1% to about 7.5%, about 3% to about 7.5%, about less than 1%to about 5%, and about 4% to about 7%.

In one embodiment, the film 10 is comprised of a co-polymer thatincludes one or more of four monomers; glycolide, lactide, caprolactone,and trimethylene carbonate. Glycolide may be included and may have theeffect of speeding up degradation of the film 10. Lactide may also beincluded and may have the effect of increasing mechanical strength offilm 10. Caprolactone and trimethylene carbonate may be used and mayhave the effect of increasing flexibility of film 10.

In one embodiment, the bioresorbable polymer includes one or more ofPLA, PGA, PCL, polydioxanone, TMC and copolymers of these. In oneembodiment, the bioresorbable polymer is produced from a copolymer ofglycolic acid, caprolactone, lactic acid, and trimethylene carbonate. Inone embodiment, the bioresorbable polymer is produced from a copolymerof approximately 60-70% glycolic acid, approximately 17-20%caprolactone, approximately 5-10% lactic acid and approximately 8-10%trimethylene carbonate. In one embodiment, the bioresorbable polymercontains repeat units selected from the group consisting of: L-lacticacid, D-lactic acid, L-lactide, D-lactide, D,L-lactide, glycolide, alactone, a lactam, trimethylene carbonate, a cyclic carbonate, a cyclicether, para-dioxanone, beta-hydroxybutyric acid, beta-hydroxypropionicacid, beta-hydroxyvaleric acid, and a combination thereof. In oneembodiment, the bioresorbable polymer contains repeat units selectedfrom the group consisting of: L-lactic acid, D-lactic acid. L-lactide;D-lactide, D,L-lactide, ε-caprolactone, trimethylene carbonate,para-dioxanone, and a combination thereof. Film 10 may also oralternatively include natural biopolymers such as alginate, chitosan,collagen, gelatin, hyaluronate, zein and others.

Still referring to FIG. 1A, the film 10 may be configured to have anypreferred dimensions including a thickness h₃ measured along thetransverse direction T between first surface 10 a and second surface 10b not inclusive of the raised lips 14 a that are illustrated in FIGS. 1Aand 1B as surrounding apertures 14. In one embodiment, film 10 issufficiently thin such that it does not interfere with the mechanicalinterlocking between the bone plate 12 and the screws that are driventhrough the film 10 and the bone plate 12 and into an underlying boneduring fixation (such as where if the film is trapped between the plateand screw). In some embodiments, thickness h₃ is minimized as much aspossible. In one embodiment, the thickness of film 10 is selected suchthat degradation of film 10 does not cause significant loosening of aconnection to bone plate 12 such as a plate-screw construct.

In some embodiments, the thickness h₃ of film 10 is approximately 0.05mm. In some embodiments, the thickness h₃ of film 10 is approximately nogreater than 0.05 mm. In some embodiments, thickness h₃ of film 10 isless than approximately 0.05 mm, for example approximately 0.04 mm. Insome embodiments, thickness h₃ of film 10 is approximately 0.06 mm. Insome embodiments, thickness h₃ of film 10 is approximately 0.07 mm. Insome embodiments, thickness h3 of film 10 is approximately 0.08 mm. Insome embodiments, thickness h₃ of film 10 is approximately 0.09 mm. Insome embodiments, thickness h₃ of film 10 is approximately 0.1 mm. Insome embodiments, thickness h₃ of film 10 is approximately 0.2 mm. Insome embodiments, thickness h₃ of film 10 is approximately 0.3 mm. Insome embodiments, thickness h₃ of film 10 is approximately 0.4 mm. Insome embodiments, thickness h₃ of film 10 is approximately 0.5 mm.

In one embodiment, the thickness h₃ of the film 10 is approximatelyuniform throughout film body 11. In some embodiments, the film 10 istapered toward one or more edges along the outer periphery 13. In someembodiments, thickness h₃ of film 10 differs in two or more sections ofthe film body 11 to control strength or drug delivery of each area.

In some embodiments, the film 10 is of sufficient strength to withstandmechanical forces such as implantation, drilling and screw placement. Inother embodiments, the film 10 has tensile properties that permit aregion of the film to tear upon penetration of a screw or other fixationelement through that region. This has the advantage of preventing thefilm from becoming entangled with or otherwise wrapped around thefixation element, which can potentially cause damage to the film andinhibit the correct placement of the fixation element. In oneembodiment, film 10 has a first tensile strength in a first planardirection and a second tensile strength in a second planar directionthat is perpendicular to the first planar direction, where the firsttensile strength is substantially equal to the second tensile strength.In one embodiment, film 10 has the strength characteristics as listed intables 1-3 below. Each of the six samples listed in the Tables belowwere films comprised of a copolymer containing approximately 70%glycolide, 17% caprolactone, 8% trimethylene carbonate, and 5% lactideby weight.

TABLE 1 Tensile strain at Film Specimen Length Width Thickness Yield(Offset Sample Start Date label (mm) (mm) (mm) 0.2%) (%) 1 07/02/2009Day 0 50.00 10.510 0.059 2.44051 9:02 AM Sample 1 2 07/02/2009 Day 050.00 11.160 0.063 3.43452 9:05 AM Sample 2 3 07/02/2009 Day 0 50.0011.230 0.062 2.04468 9:07 AM Sample 3 4 07/02/2009 Day 0 50.00 10.7400.057 2.81023 9:09 AM Sample 4 5 07/02/2009 Day 0 50.00 11.180 0.0663.06678 9:13 AM Sample 5 6 07/02/2009 Day 0 50.00 10.920 0.058 3.659449:15 AM Sample 6 Mean 50.00 10.957 0.061 2.90936 Standard 0.000 0.2880.003 0.607 Deviation Coefficient 0.000 2.625 5.639 20.854 of Variation

TABLE 2 Tensile Tensile Tensile Tensile stress at strain at stress atstrain at Yield Maximum Maximum Break Film (Offset 0.2%) Load Load(Standard) Sample (MPa) (%) (MPa) (%) 1 13.75364 22.50031 26.3116531.66499 2 14.00508 31.66468 27.57964 49.99874 3 9.25147 32.4984326.60082 149.99967 4 12.82553 26.66562 28.46340 55.83280 5 13.5306023.33406 26.59371 36.66562 6 12.60631 35.83187 26.79990 212.49840 Mean12.66211 28.74916 27.05819 89.44337 Standard 1.756 5.393 0.812 74.322Deviation Coefficient 13.865 18.760 3.000 83.094 of Variation

TABLE 3 Tensile stress at Break Film (Standard) Modulus (AutomaticSample (MPa) Young's) (MPa) 1 15.20147 749.15765 2 21.71590 504.50877 319.08817 657.83084 4 18.08469 574.31825 5 18.71550 618.69300 6 21.75346436.82724 Mean 19.09320 590.22262 Standard 2.460 111.150 DeviationCoefficient 12.885 18.832 of Variation

In one embodiment, film 10 has a tensile strain at yield (Offset 0.2%)of approximately 2% to approximately 4% and/or a mean tensile strain ofapproximately 3%. In one embodiment, film 10 has a tensile stress atyield (Offset 0.2%) of approximately 9 MPa to approximately 14 MPa,and/or a mean tensile stress at yield of approximately 12.5 MPa. In oneembodiment, film 10 has a tensile stress at maximum load ofapproximately 25 MPa to approximately 30 MPa, and/or a mean tensilestress at maximum load of approximately 27 MPa. In one embodiment, film10 has a tensile strain at break (standard) of approximately 30% toapproximately 215%, and/or a mean tensile strain at break ofapproximately 89%. In one embodiment, film 10 has an automatic Young'smodulus of approximately 430 MPa to approximately 750 MPa, and/or a meanautomatic Young's modulus of approximately 590 MPa. Film 10 may becharacterized by combination of one or more of the foregoing properties.

Referring to FIGS. 1A, 1B, 2, 11K and 11L, in some embodiments, film 10includes a plurality of apertures or apertures 14. In one embodiment,the apertures 14 allow the passage or transport of fluids through film10 (e.g., when implanted near living tissue). In some embodiments, itmay be important to allow for fluid flow from one side of the sleeve tothe other (inside to outside) in order, for example, to avoid creating a“dead space” between the film 10 and the bone plate 12. Additionally,the apertures 14 may advantageously provide more even distribution ofthe drug or biological agent to adjacent tissue and bone as the materialleaches out of the polymer than a sleeve without such apertures.

The apertures 14 may be configured to be any size and shape, includingvariations within the same polymer film. In one embodiment, apertures 14are defined by substantially cylindrical sidewalls. In some embodiments,apertures 14 have sidewalls that have segments that are inwardly facingconvex surfaces. In some embodiments, the inwardly facing convex surfaceis substantially parabolic. Apertures 14 need not be perfectly round incross section, and in some embodiments, may be ovoid, elliptical, staror diamond in shape. In some embodiments, apertures 14 extend to one ormore apexes. In one embodiment, such apexes promote tears in film 10during use (e.g., where a zone of weakness is created by the aperture).In one embodiment, apertures 14 extend completely through sheet 12 fromthe first surface 10 a to the second surface 10 b (see FIG. 4C). In oneembodiment, one or more of the apertures 14 can extend only partiallythrough film 10, for instance from the second surface 10 b toward butnot to the first surface 10 a, to control drug release or increase theinitial strength of the film 10. In certain embodiments, the film 10 mayhave a first one or more regions having the apertures 14 and a secondone or more regions devoid of the apertures 14. A film region can bedefined as any single contiguous area, substantially either ellipticalor quadrangular, of at least 10% of the total surface area of filmsurface 10 a or 10 b. According to one embodiment, one or more regionshaving apertures 14 can be separated by one or more regions having noapertures 14. According to another embodiment, a region having aperturesis contiguous, and in a further embodiment a region having no aperturesis contiguous. For example the periphery of the film 10 can haveapertures while the remainder of the film is devoid of apertures, oralternatively a periphery of film 10 can be devoid of apertures whilethe remainder of the film has apertures. It should be appreciated thatthe distribution pattern can be configured as desired to include more orless apertures in any one region of the film, as well as permitting aneven or regular distribution of apertures throughout the film.

The apertures 14 may be configured to allow for any desired porosity offilm 10. In one embodiment, the porosity of the film 10 is the range ofapproximately 1% to approximately 30%, in another embodimentapproximately 5% to about 25%, in another embodiment approximately 10%to about 20%, and in a preferred embodiment is approximately 15%. In oneembodiment, the porosity of film 10 is greater than approximately 1%. Inone embodiment, the porosity of film 10 is greater than approximately2%. In one embodiment, the porosity of film 10 is greater thanapproximately 3%. In one embodiment, the porosity of film 10 is greaterthan approximately 4%. In one embodiment, the porosity of film 10 isgreater than approximately 5%. In one embodiment, the porosity of film10 is greater than approximately 6%. In one embodiment, the porosity offilm 10 is greater than approximately 7%. In one embodiment, theporosity of film 10 is greater than approximately 8%. In one embodiment,the porosity of film 10 is greater than approximately 9%. In oneembodiment, the porosity of film 10 is greater than approximately 10%.In one embodiment, the porosity of film 10 is greater than approximately11%. In one embodiment, the porosity of film 10 is greater thanapproximately 12%. In one embodiment, the porosity of film 10 is greaterthan approximately 13%. In one embodiment, the porosity of film 10 isgreater than approximately 14%. In one embodiment, the porosity of film10 is greater than approximately 15%. In one embodiment, the porosity offilm 10 is greater than approximately 16%. In one embodiment, theporosity of film 10 is greater than approximately 17%. In oneembodiment, the porosity of film 10 is greater than approximately 18%.In one embodiment, the porosity of film 10 is greater than approximately19%. In one embodiment, the porosity of film 10 is greater thanapproximately 20%.

Referring to FIG. 11L, in one embodiment, the apertures 14 have anaverage maximum cross-sectional length (e.g., diameter) in the range ofapproximately 0.1 mm to approximately 1.5 mm, such as approximately 0.1mm to 1.0 mm, 0.1 mm to 0.5 mm, 0.5 mm to 1.5 mm, 0.5 mm to 1.0 mm, 0.1mm to 0.75 mm, 0.5 mm to 0.75 mm, 0.75 mm to 1.0 mm, and 0.75 mm to 1.5mm. In a preferred embodiment apertures 14 have an average maximumcross-sectional length (e.g., diameter) of about 0.75 mm. In oneembodiment, apertures are spaced apart from adjoining apertures in therange of approximately 0.5 mm to about 5 mm. such as approximately 0.5mm to approximately 2.5 mm, 2.5 mm to 5.0 mm, 1.0 mm to 2.0 mm, 1.5 mmto 2.0 mm, 0.5 mm to 1.0 mm, 0.5 mm to 1.75 mm, and 1.0 mm to 1.75 mm.In a particularly preferred embodiment, apertures have an averagemaximum cross-sectional length of 0.75 mm and a spaced apartapproximately 1.75 mm. In a preferred embodiment, apertures 14 arespaced apart approximately 1.75 mm. In one embodiment, the apertures 14are arranged in a regular array (e.g., aligned rows and columns asillustrated in FIG. 11K). In one embodiment, the apertures 14 arearranged in an irregular array. Thus, the apertures 14 can generally beconfigured such that a diameter of the threaded shaft of the bone screwthat is driven through the film 10, an aligned bone fixation hole of thebone implant, and the underlying bone, is greater than both thecross-sectional dimensions of the apertures 14 and the gap betweenadjacent apertures 14, such that a given screw shaft is configured to bedriven through a region of the film 10 that includes more than oneaperture 14. It should be appreciated that the shaft of the bonefixation screw can be driven through at least one of the apertures 14,such as a plurality of the apertures 14, through the aligned boneimplant hole, and into the underlying bone. The step of driving thescrew shaft through at least one or more of the apertures 14 candecrease random unpredictable tearing of the film compared to a step ofdriving the screw shaft through a region of the film 10 that is devoidof apertures 14.

Referring to FIGS. 1A, 1B and 4C, in some embodiments, the first surface10 a can define a contiguous planar portion 15 and interfaces, which canbe configured as solidified meniscuses 17 as described below, thatadjoin the contiguous planar portion 15 and one or more interiorsurfaces that define a respective one of the apertures 14. In accordancewith one embodiment, one or more of the meniscuses 17 can be configuredas a raised lip 14 a that extends out with respect to the contiguousplanar portion 15 (e.g., along a direction from the second surface 10 btoward the first surface 10 a) along the transverse direction T, andthus extends out from the first surface 10 a. A benefit of the raisedlip 14 a around each aperture 14 may include providing a reinforcementor grommet to each aperture 14, effectively increasing the mechanicalstrength of the film 10 relative to a similar perforated film that isdevoid of raised lips 14 a. A further benefit of the raised lips 14 amay include a texture on the first surface 10 a. Such a texture may bean advantage for tactile feel or for the purpose of increasing (orreducing) friction of the first surface 10 a of the film 10 when, forexample, the first surface 10 a is in contact with another surface. Inone embodiment, the raised lips 14 a decrease the tendency of the film10 to adhere to a surface such as the metal surface of an implant,making it easier to slide a sleeve made from the film 10 onto the boneplate 12. In one embodiment, the lips 14 a provide stand-off between thebone plate 12 and the film 10, thereby reducing the surface area of thefilm 10 that is in contact with the bone plate 12.

In one embodiment, the contiguous planar portion 15 extends between theplurality of raised protruding lips 14 a, for instance from each of theraised lips 14 a to others of the raised lips 14 a. In one embodiment,the raised lips 14 a are substantially in the shape of the outer surfaceof an impact crater. In one embodiment, the raised lips 14 a define acontinuous concave outer surface. In one embodiment, the concave outersurface is a parabolic concave surface. In one embodiment, one or moreof lips 14 a (or, in some embodiments, each lip 14 a) has a concaveouter surface and an opposed convex inner surface, either or both ofwhich are parabolic in shape. In one embodiment, the lips 14 a can eachhave an edge that is raised above the contiguous planar portion 15 offirst surface 10 a by approximately 0.1 mm to approximately 1.0 mm. Inone embodiment, lips 14 a each have an edge that is raised above thecontiguous planar portion 15 of first surface 10 a by approximately 0.1mm. In one embodiment, lips 14 a each have an edge that is raised abovethe contiguous planar portion 15 of first surface 10 a by approximately0.2 mm. In one embodiment, lips 14 a each have an edge that is raisedabove the contiguous planar portion 15 of first surface 10 a byapproximately 0.3 mm. In one embodiment, lips 14 a each have an edgethat is raised above the contiguous planar portion 15 of first surface10 a by approximately 0.4 mm. In one embodiment, lips 14 a each have anedge that is raised above the contiguous planar portion 15 of firstsurface 10 a by approximately 0.5 mm. In one embodiment, lips 14 a eachhave an edge that is raised above the contiguous planar portion 15 offirst surface 10 a by approximately 0.6 mm. In one embodiment, lips 14 aeach have an edge that is raised above the contiguous planar portion 15of first surface 10 a by approximately 0.7 mm. In one embodiment, lips14 a each have an edge that is raised above the contiguous planarportion 15 of first surface 10 a by approximately 0.8 mm. In oneembodiment, lips 14 a each have an edge that is raised above thecontiguous planar portion 15 of first surface 10 a by approximately 0.9mm. In one embodiment, lips 14 a each have an edge that is raised abovethe contiguous planar portion 15 of first surface 10 a by approximately1.0 mm.

In one embodiment, the lips 14 a impart a first tactile feel to thefirst surface 10 a that is different (e.g., distinguishable by a surgeonwearing a surgical glove) from a second tactile feel of second surface10 b that is devoid of the lips 14 a. In one embodiment, apertures 14 inone or more areas on first surface 10 a each are bounded by a raised lip14 a and apertures 14 in one or more other areas on first surface 10 aare not so bounded. In one embodiment, the solidified meniscus 17 candefine a height h₄ (see FIG. 4C) from the second surface 10 b to theoutermost end of the raised lips 14 a. The height h₄ can be defined bythe raised lips 14 a, and can be uniform across the first surface 10 ain accordance with one embodiment. In one embodiment, at least one ofthe raised lips 14 a has a height h₄ that is different than the heighth₄ of at least one other of the raised lips 14 a. In one embodiment, oneor more apertures 14 are bounded by a lip 14 a on one or both firstsurface 10 a and second surface 10 b. An embodiment such as the oneillustrated in FIG. 1A, may include a single continuous lip 14 a thatsurrounds each aperture 14. The continuous lip may be substantiallyuniform in thickness and/or substantially uniform in height relative toany one aperture, or from aperture 14 to aperture 14. The apertures 14may be evenly spaced apart across all or at least a portion of the film10. In other embodiments, at least a portion of the film 10 ischaracterized by apertures 14 that are spaced apart in at least twodifferent spacing configurations, so as to define two different patternsof apertures 14.

In some embodiments, the film 10 includes one or more drugs or othersubstance for delivery in the body. Such drugs include, but are notlimited to, antimicrobial agents, anti-fibrotic agents, anesthetics andanti-inflammatory agents as well as other classes of drugs, includingbiological agents such as proteins, growth inhibitors and the like. Infurther embodiments, the film 10 can include one or more biocompatibleparticles. The particles, according to one embodiment, can assist inbone remodeling and regrowth. For example, in certain embodiments,particles are calcium-containing salt particles, such as calciumphosphate or calcium sulfate particles. These calcium salts are wellknown for use at bone remodeling and regrowth sites. Other potentialbiocompatible particles can include salts or oxides containing, forexample, silicon, magnesium, strontium, and zinc. In certainembodiments, the particles are at least partially insoluble and can besubstantially insoluble in the polymer film. In embodiments where theparticles are insoluble in the film, the particles provide heterogeneousnucleation sites in the polymer film. Such nucleation sites can increasethe rate of crystallization of the film as well as increasing theoverall crystallinity of the film as compared to the film without suchnucleation sites. Altering the crystallinity properties of a polymerfilm can be desired where a decrease in elastic behavior is preferred.For example, FIGS. 12 and 13 (and explained more fully below) show thedecrease in elongation and yield properties of a plain polymer film uponthe incorporation of insoluble biocompatible particles (in this case, 5%and 10% addition of insoluble gentamicin sulfate particles).Additionally, an increase in crystallinity can be a factor thatpotentially slows the degradation rate of a biodegradable polymer film.

In one embodiment, the film 10 includes an active agent, such as a drugor drugs. The active agent may be an anti-microbial agent, for instancean antibiotic, anti-viral agent, or anti-parasitic agent, though aspreviously mentioned, it should be appreciated that other active agentstypically used in conjunction with orthopedic surgery are alsocontemplated within the scope of this disclosure, including, forexample, anti-inflammatory drugs, steroids, analgesics, opioids, growthfactors, and the like. In embodiments including an antibiotic, theantibiotic selected may be active against the majority of bacteria foundin orthopedic implant related infections. These include primarilystaphylococci, and Gram negative bacilli.

In one embodiment, the drug selected is stable during the manufacturingprocess that fabricates the film. Depending upon the manufacturingprocesses utilized, the polymer formulation of the film, the preferreddrug, and the pharmaceutical formulation of the preferred drug (e.g.,the particular pharmaceutical salt utilized) the drug can either besoluble or insoluble with the polymer formulation. In embodiments wherethe drug is at least partially—including being substantially—insolublein the polymer, the film can physically entrap the drug particles. Inembodiments where the drug is at least partially—including beingsubstantially—soluble with the polymer, the film can chemically bondwith and to the drug. In certain embodiments, the film can bothphysically entrap and chemically bond with and to the drug

In one embodiment, film 10 includes gentamicin sulfate. Gentamicinsulfate is thermally stable above 100° C., and is stable to organicsolvents including DMSO, which is used in the manufacturing process insome embodiments. Gentamicin sulfate is active against many bacteriacommonly associated with orthopedic infection, such as Staphylococcusaureus including MRSA, coagulase negative staphylococci, and Gramnegative rods such as Pseudomonas and Enterobacter species. Withoutbeing bound by any particular theory, it is believed that local deliveryof gentamicin to a fracture site containing a metallic implant may beeffective in preventing infection by some bacteria which areintermediate or resistant to systemic levels of gentamicin because ofthe locally higher concentrations of gentamicin at the fracture site.

Referring to FIGS. 4A-4C, in one embodiment, film 10 comprises a drugthat is at least partially insoluble and can be substantially insolublein the film, such that the drug can serve as a biocompatible particlethat provides a heterogeneous nucleation site as previously mentioned.In a further embodiment, film 10 comprises a plurality of discreteeluting drug components 30. In one embodiment, film 10 is configured toelute the plurality of discrete drug components 30 at different timeperiods following implantation. In one embodiment, the elution of drugcomponents 30 (e.g., an antibiotic such as gentamicin) in vivo is atwo-phase process, with a burst release occurring as soon as film 10contacts water or body fluid, and a second phase which is controlled bythe degradation rate of the polymer. In some embodiments, it isdesirable to have an initial burst release of gentamicin to reducebacterial contamination of the wound site on initial implantation, thena lower level release of gentamicin for a period of days to weeksafterward, to prevent growth and/or biofilm formation of any survivingbacteria. In one embodiment, film 10 is configured to elute up toapproximately 20 percent of the drug within the first hour afterimplantation. In another embodiment, film 10 is configured to elute upto approximately 60 percent of the drug contained within film 10approximately 1 week after film 10 has been implanted in contact withliving tissue. In another embodiment, film 10 is configured to elute upto approximately 100% of the drug within 10 days after implantation. Inone embodiment, the combination of particle size and polymer degradationrate control the drug release profile, and create the desired 2-phaserelease. In one embodiment, the drug is released over a 2 to 3 week timeperiod. In other embodiments, the drug is released over a shorter orlonger time frame.

In one embodiment, where the drug is insoluble with the film, therelative amounts of drug released during these two phases are controlledby the particle size of the drug in the film. In one embodiment, drugcomponents 30 are evenly distributed throughout film 10, and any drugcomponents 30 in contact with a surface of film 10 are dissolved morerapidly than a drug component 30 that is not in contact with a surfaceof film 10. In one embodiment, a quantity of drug components 30 that arein contact with a surface of film 10 upon implantation are configured torelease in a burst upon implantation. In one embodiment, the larger thesize of drug components 30, the higher the proportion of drug components30 in contact with the surface, and the greater the burst release. Forthis reason, the size of drug components 30, in one embodiment, is keptunder 10 microns in diameter which reduces the burst release toapproximately 20 to 35% of the total drug content. In one embodiment,drug components 30 are under 20 microns in diameter.

In one embodiment, film 10 is configured to deliver multiple drugs fromone or more independent layers, some of which may contain no drug. Incertain embodiments, one or more of the layers may be a drug containinglayer and/or a rate controlling layer for drug release (with or withouta drug contained therein). In another embodiment, film 10 may include aplurality of drug components each being characterized by a differentrelease rate from film 10 such that a first drug is associated with afirst release profile that is different from a second release profile ofa second drug.

Where the film contains one or more antibiotics that can release fromthe film into the surgical site environment over a period a time, a Zoneof Inhibition (ZOI) can be formed around the film where certainbacterial growth cannot occur due to the presence of the antibioticcontaining film. Where the film defines a central axis or center point,the ZOI is defined as the radial distance extending in three dimensionsfrom the central axis or center point where bacteria will not colonize.According to one embodiment, the film has a ZOI of at least 12 mm.According to one embodiment, where the film includes the antibioticgentamicin (13% by weight), the film has a ZOI of at least 20 mm wherethe bacteria are selected from S. aureus, S. epidermidis, Pseudomonasaeruginosa, or Enterobacter cloacae, or combinations thereof

Accordingly, when the film 10 defines a cover suitable for use incombination with a medical implant, the cover does not have to overlaythe entire surface area of an implant to be effective, and can thusoverlay at least a portion of the surface area of one or both sides(e.g., the bone-facing side and the side opposite the bone-facing side)of the implant up to an entirety of the surface area of one or bothsides of the implant. For example, in those cases where at least onefilm 10 defines a cover configured as a polymer film sleeve 31 (see,e.g., FIGS. 11A-J) designed to completely cover an implant, such as thebone plate 12, the film 10 may be torn or damaged during fracturereduction and plating, or otherwise does not cover the entire surface ofthe implant. Alternatively, the sleeve can be designed to cover only aportion of the implant. In this manner, a surgeon can determine anappropriate zone of inhibition needed for a particular surgical siteand/or medical implant, and utilize the polymer film accordingly, e.g.,utilize the appropriate length and/or quantity of polymer film.

Referring to FIGS. 3A-10, there are shown devices used in a method ofmanufacturing films 10 in accordance with exemplary embodiments of thepresent disclosure.

In one embodiment, a manufacturing method creates polymer films 10 fordrug delivery. In one embodiment, the film 10 is solvent cast. In someembodiments, solvent casting methods are advantageous in the fabricationof films 10 that contain a drug component 30 that could be potentiallydamaged by the heat and shear of melt processes such as blown filmextrusion. Producing films 10 using a punch press (e.g., with manyhundreds or thousands of holes or holes with complicated geometry) mayalso be time consuming and expensive.

In some embodiments, methods described herein can create the thin films10 and the apertures 14 in a single step. In some embodiments, methodsdescribed herein create the film 10 and thousands of apertures 14 withinthe periphery of the film with accurate predetermined control ofgeometry and placement of the apertures 14 and accurate predeterminedcontrol of the thickness of the film 10.

Referring to FIGS. 3A-3G, in some embodiments, the film 10 is cast in amold 18. In one embodiment, mold 18 includes a plurality of protrusionsor posts 20 extending from a bottom 18 a of mold 18. When polymericsolution is deposited in the mold 18, the posts 20 occupy space thatdefines the apertures 14 when the polymeric solution solidifies intofilm 10. In one embodiment, the mold 18 is comprised of injection moldedpolypropylene. The mold 18 may be manufactured from other materials,including polymers (see FIG. 3F), glass, metals (see FIG. 3G) orceramics. In one embodiment, the mold 18 is comprised of two or morematerials. For example, the bottom 18 a of the mold 18 may be made frommetal with a polymer coating to reduce adhesion of the cast film to themold and/or to form posts 20. The cavity in the mold may be formed by acasting process, a compressing molding process, an injection moldingprocess, a chemical etching process or a machining process.

In one embodiment, the mold 18 includes a cavity depth of approximately0.25 mm. In one embodiment, a distance from the bottom of the mold 18 toa top of each of the plurality of the posts 20 is equal to the cavitydepth (i.e., the height of peripheral wall 22) or vice versa. In oneembodiment, the posts 20 are longer than the desired thickness of thefilm 10. In one embodiment, the posts 20 extend 0.3 mm from the bottom18 a of the mold 18. In one embodiment, posts 20 extend 0.2 mm from thebottom 18 a of the mold 18. In one embodiment, the posts 20 extend 0.25mm from the bottom 18 a of the mold 18. In one embodiment, the posts 20extend 0.3 mm from the bottom 18 a of the mold 18. In one embodiment,the posts 20 extend 0.35 mm from the bottom 18 a of the mold 18. In oneembodiment, the posts 20 extend 0.4 mm from the bottom 18 a of the mold18. In one embodiment, the posts 20 extend 0.45 mm from the bottom 18 aof the mold 18. In one embodiment, the posts 20 extend 0.5 mm from thebottom 18 a of the mold 18.

In one embodiment, the posts 20 are arranged to produce a predeterminedselected size, shape, pattern, and arrangement of the apertures 14described above. In one embodiment, a perimeter form or peripheral wall22 of the mold 18 defines a total mold area, and the plurality of posts20 define an area that is substantially equal to or corresponding to theultimate porosity of the film 10.

In one embodiment, the mold 18 includes a trough 24 that extends atleast partially around the peripheral wall 22 of mold 18. In oneembodiment, the trough 24 extends around the entire peripheral wall 22of mold 18. In some embodiments, the trough 24 retains any excesspolymer that flows or is urged from the cavity of the mold over theperipheral wall 22. In one embodiment, the mold 18 includes an extension40, which can define a handle that extends out from at least one outeredge of the mold 18. In one embodiment, the extension 40 is provided forgrasping and manipulating the mold 18 without contacting the polymersolution that is disposed within the mold 18.

According to the present disclosure, there is a method of producing apolymer film comprising: placing a polymer solution into a mold having aplurality of protrusions extending from a bottom of the mold. In certainembodiments, the polymer solution is characterized by a viscosity thatinhibits the unaided flow of the polymer throughout the mold. Theprocess further includes urging the polymer solution around each of theplurality of protrusions; and solidifying the polymer solution. In oneembodiment, the mold includes a perimeter form extending to an elevationthat is substantially equal to an elevation of each of the plurality ofprotrusions. In one embodiment, the urging comprises drawing an urginginstrument such as a blade, bar, squeegee or roller across the perimeterform and the plurality of protrusions to force the polymer solution toflow around the plurality of protrusions and throughout the mold suchthat the polymer solution has a substantially uniform thickness. In oneembodiment, at least a portion of an outer surface of a protrusion, forexample an upper portion of a protrusion, is substantially free ofpolymer solution after the drawing. In one embodiment, the placing stepincludes depositing the polymer solution in the mold such that a portionof the polymer solution is above the elevation of the perimeter form andthe protrusions. In still further embodiments, one or more of the methodsteps can be repeated such that the method can produce a film comprisinga plurality of layers, for example, two or more layers, such as twolayers, three layers, four layers, up to and including seven layers. Incertain embodiments the method additionally includes the steps ofplacing one or more additional polymer solutions (for example, placingan additional polymer solution, placing a second additional polymersolution, placing a third additional polymer solution, up to andincluding placing a sixth additional polymer solution) in the mold overa first polymer solution, and urging the one or more polymer solutionsaround each of the plurality of protrusions. The step of placing one ormore polymer solutions in the mold can occur prior to, during, or afterthe step of solidifying the polymer solution. Thus, according to oneembodiment of the method, each of the one or more polymer solutionsplaced in the mold can solidify prior to, during, or after, the step ofplacing the next or subsequent additional polymer solution into the mold(e.g., placing a third additional polymer solution into the mold priorto, during, or after, solidifying the second additional solution; orplacing an additional polymer solution into the mold prior to, during,or after solidifying a first polymer solution). According to anotherembodiment, all of the polymer solutions placed into the mold cansolidify substantially simultaneously. According to one embodiment, theone or more polymer solutions comprise a polymer solution that cansolidify into an adhesive layer, and according to another embodiment,the one or more polymer solutions comprise a rate controlling layer fordrug release.

In one embodiment, a polymer solution 28 is formed. The polymer solution28 is placed in the cavity of the mold 18 so as to create the film 10.In some embodiments where the drug is insoluble in the polymer, asolvent and drug component 30 are first mixed to form a well distributedsuspension, and then polymer is added and dissolved in the solvent/drugsuspension. In other embodiments, the polymer is dissolved in thesolvent and then the insoluble drug is added to the solution at thedesired amount. In still other embodiments, the drug is soluble in thepolymer/solvent solution. In embodiments where aliphatic polyesterscomprise the polymer formulation, typically a polar solvent will beused. Suitable polar solvents can include dimethyl sulfoxide (DMSO),tetrahydrofuran (THF), alcohols, acetone, ethyl acetate, acetonitrile,dimethylformamide (DMF), and formic acid. In one embodiment, a polymermaterial is dissolved at a 4:1 solvent to polymer ratio in dimethylsulfoxide (DMSO) at elevated temperature and the drug gentamicin sulfateis added at 13% by weight. In one embodiment, polymer solution 28 isformed by introducing drug units 30 to a polymer/solvent blend at atemperature below 90° C. In one embodiment, polymer solution 28comprises a cross-linkable pre-polymer such as polyurethanes,polyfumarates, polymethacrylates, etc.

Referring to FIGS. 4A, 6 and 8, once the polymer solution 28 isprepared, polymer solution 28 is placed into the mold 18, which can be aone sided mold as illustrated. In some embodiments, the viscosity ofpolymer solution 28 and/or the density of posts 20 substantiallyinhibits the unaided flow of the polymer 28 throughout the mold 18. Inone embodiment, after adding polymer solution 28 to mold 18, the topsurface of polymer solution 28 is a height h₂ above the base 18 a ofmold 18 which is greater than a height h₁ of the mold cavity and posts20.

Referring to FIGS. 4B, 7 and 9, after the polymer solution 28 has beenadded to the mold 18, in one embodiment, the polymer solution 28 can beurged around each of the plurality of posts 20 in the cavity of the mold18. For instance, any suitable urging instrument 26 can urge the polymersolution around each of the plurality of posts 20. In one embodiment,urging instrument 26 can be, for example, a blade, bar, squeegee orroller that slides, or the mold 18 is moved relative to urginginstrument 26, across the perimeter wall 22 and over the posts 20 toforce polymer solution 28 to flow around posts 20 and throughout mold 18such that polymer solution 28 has a substantially uniform thickness. Inone embodiment, drawing the urging instrument 26 across mold 18 causesthe urging instrument 26 to remove excess polymeric film material fromthe top surface of posts 20. In one embodiment, an outer surface, suchas an upper surface, of one or more posts 20 is substantially free ofpolymer solution 28 after the drawing.

Referring to FIG. 4C, once the polymer solution 28 is drawn or spreadthroughout mold 18, the polymer solution 28 is solidified to form thefilm 10. In one embodiment, the mold 18 can be placed into a solventdrying oven at an elevated temperature to remove the solvent, leavingbehind a thin cast film. In one embodiment, the polymer solution 28 issolidified by cross-linking the polymer by applying UV radiation,temperature change, polymerization catalysts, soluble crosslinkingagents or combinations thereof to the polymer solution 28. In oneembodiment, the solidifying step includes exposing the mold 18containing the polymer solution 28 to a second solvent. In oneembodiment where, for example, the polymer solution 28 includes polymer,a drug and a first solvent, the first solvent is soluble in the secondsolvent, but the polymer and drug component are not soluble in thesecond solvent. Thus, by exposing the polymer solution 28 to the secondsolvent, the first solvent is removed from the polymer solution leavingthe polymer and the drug product to solidify to form, for example, thefilm.

In one embodiment, solidifying the polymer solution reduces a thicknessof the polymer solution from a first thickness h₁ to a second thicknessh₃. In one embodiment, solidifying the polymer solution reduces athickness of the polymer solution proximate to posts 20 from a firstthickness h₁ to a second thickness h₄. In one embodiment, the thicknessh₄ of the film 10 proximate the posts 20 is greater than the thicknessh₁ of the film 10 between the posts 20. In one embodiment, the lips 14 acan be created due to the polymer solution forming a meniscus aroundeach of posts 20 during solidifying of the polymer solution 28 to formthe film 10. In one embodiment, the meniscuses formed about the posts 20define the lips 14 a when the polymer solution 28 has solidified. In oneembodiment, height h₄ of lips 14 a may be controlled by carefulselection of the material and geometry of the posts 20 or by coating theposts 20 with, for example, a lubricious material such as afluoropolymer or silicone mold release. In one embodiment, the height h₄of the lips 14 a is controlled by the concentration of the polymersolution.

Referring to FIGS. 4C-4E, the material that forms the posts 20 canaffect the configuration of the solidified meniscus 17 between theapertures 14 and the contiguous planar portion 15, such as the formationof lips 14 a around apertures 14. The height of the lips 14 a relativeto the contiguous planar portion 15 is the difference between h₄ and h₃,and can be the result of a meniscus of the polymer solution 28solidifying around posts 20. The meniscus can be defined by the curve inthe upper surface of the polymer solution near the posts 20 and iscaused by surface tension between the polymer solution 28 and therespective posts 20. The polymer solution 28 can have either a convex orconcave meniscus at posts 20. A concave meniscus, which creates theraised lips 14 a, can occur when the molecules of the polymer solutionare attracted to the material of the posts 20 (commonly known asadhesion) such that the level of the polymer solution is higher aroundthe posts 20 than the solution generally. According to one embodiment,as shown in FIG. 4C, the posts 20 comprise materials configured to causea concave meniscus in polymer solution, where h₄ is greater than h₃.Conversely, a convex meniscus occurs when the molecules of the polymersolution have a stronger attraction to each other (commonly known ascohesion) than to the material of the posts 20. According to oneembodiment, as shown in FIG. 4D, the posts 20 comprise materialsconfigured to create a convex meniscus in polymer solution where h₃ isgreater than h₄. Thus, it should be appreciated that the meniscuses 17between the contiguous planar portion 15 and the apertures 14 can beconfigured as raised lips 14 a that extend out from the second surface10 b in the manner described above, or can be configured as depressionsthat are recessed into the second surface 10 b along a direction fromthe first surface 10 a toward the second surface, from the contiguousplanar portion 15 to respective ones of the apertures 14. According to afurther embodiment as shown in FIG. 4E, the posts 20 comprise materialsconfigured to cause minimal to no meniscus (e.g., substantially nomeniscus) of the polymer solution, such that where h₄ is substantiallyequal to h₃ at the meniscus 17.

Referring to FIG. 10, once the polymer solution 28 is solidified, thefilm 10 is peeled out of the mold 18, such that the meniscuses formedduring the casting of the polymer solution 28 define the solidifiedmeniscuses 17.

Referring to FIGS. 5-7, a method of producing film 10 may include anautomated or partially automated casting machine 42. In one embodiment,the automated casting apparatus includes one or more computers 44 havingone or more processors and memory (e.g., one or more nonvolatile storagedevices). In some embodiments, memory or computer readable storagemedium of memory stores programs, modules and data structures, or asubset thereof for a processor to control and run the various systemsand methods disclosed herein. In one embodiment, a computer readablestorage medium having stored thereon computer-executable instructionswhich, when executed by a processor, perform one or more of the methodsdisclosed herein.

The film 10 may be manufactured by alternative methods. In oneembodiment, the polymer solution 28 can be cast onto perforated filmmaterial with a backing blotter layer, and then the perforated film isremoved from the blotter layer, removing the cast solution where therewere holes in the casting sheet. One difference with such a process fromthe above described processes is that, in some embodiments, it does notcreate a raised lip 14 a and apertures 14.

In another embodiment, porous films 10 may also be formed by alyophilization or freeze-drying method. In one embodiment, a thin solidfilm of polymer solution is cast in a mold, then the mold chilled to atemperature below the freezing point of the solution, then placed undervacuum to remove the solvent from the film. In some embodiments, thisprocess will also produce fine pores which are much smaller than theapertures 14 described in some of the embodiments above.

In one embodiment, the polymer material used for film 10 can be acrosslinkable prepolymer liquid and urged or drawn to fill the mold andremove excess material in the manner described above, then crosslinkedin place by UV radiation, temperature, a catalyst or other means. In oneembodiment, this process could produce a very similar final product asdescribed above, except that the final thickness of the cast film 10 canbe substantially equal to the depth of the mold, and there would belittle or no lip 14 a around the apertures 14.

In another embodiment, the film 10 can be produced as a thin porous filmin a screen printing process. In one embodiment, a layer of solution isscreen printed in the final pattern, then dried. In one embodiment, thisproduces a much thinner layer, however multiple layers of polymer can bescreen printed and dried one on top of the other to build up the desiredthickness of film 10, which can define a multi-layered film.

In another embodiment, a similar casting process could be performed asdescribed above using a glass plate with a pattern made from ahydrophobic polymer such as silicone, in the shape of the desiredapertures. In one embodiment, when a thin layer of polymer solution iscast onto the plate, the surface tension differences between the glassand the patterned polymer cause the solution to concentrate on the glasssurface, and pull away from the patterned hydrophobic polymer surface.In one embodiment, the solution is then dried to form a solid film withapertures in the same pattern as the silicone polymer. In oneembodiment, this process could also be performed with a crosslinkableprepolymer liquid as described above.

In another embodiment, a thin porous polymer film is made using atwo-sided mold, where the polymer solvent solution is injected into themold, and chilled to solidify the solution. In one embodiment, the moldis then opened and one side removed, leaving the chilled solution in thecavity side. In one embodiment, the chilled solution side is placed intoan oven to dry the polymer solution and form a film 10.

According to one embodiment of the disclosure, the film furthercomprises an adhesive layer, which is biocompatible, and capable ofadhesively fixing at least one surface of the film to another surface(e.g. an outer surface of a medical device). In one embodiment,substantially all of the first or second surface of the film, or bothhas an adhesive layer. In another embodiment, only a portion of thefirst or second surface of the film, or both has an adhesive layer, forexample along the periphery of the first or second surface or both. Theadhesive layer can be formed integrally with the film during the solventcasting process. In such a process the adhesive can be applied to themold and the polymer solution subsequently cast on top of the adhesivelayer. Alternatively, the polymer solution can be cast in the mold firstand the adhesive layer applied over the polymer. In certain embodiments,the polymer solution itself can comprise the adhesive layer. Of course,where it is desired to have the adhesive applied to both surfaces of thefilm, the adhesive layer can be applied in both manners. In still yetanother embodiment, the film can be solution cast molded and separatelyhave the adhesive layer applied after removal from the mold, for exampleby dipping, spraying, or coating the adhesive onto the film.

According to one embodiment where the film contains a surface adhesivelayer as previously described, a film storage system, for the storage,packaging and/or shipment of the film can include 1) the film containingan surface adhesive layer, and 2) a non-adhesive backing material (e.g.,a strip) that can be placed over the surface adhesive layer to protectand shield the adhesive layer until such time as it is desired toadhesively affix the film to the surface of another object, such as, forexample, a surface of a medical device or a tissue such as bone. At suchtime, a user, preferably a surgeon or nurse, can remove the non-adhesivebacking material and apply the film as desired. According to anotherembodiment where the film contains a surface adhesive layer, a filmstorage system, for the storage, packaging and/or shipment of the filmcan include 1) the film containing a surface adhesive layer, and 2) acollector where the film can be collected. For example, film 10 can bewound around a collector such as a cylinder and collected and stored ina rolled configuration until such time as it is desired to adhesivelyaffix the film to the surface of a medical device or surface of atissue. At such time, a user, preferably a surgeon or nurse, can unwinda length of film as identified and cut or otherwise separate the desiredlength of film from the cylinder and apply the film as desired.

In other embodiments, film 10 can be applied to a desired anatomicalsite and secured at the site without the use of an adhesive layer, or inconjunction with an adhesive layer. For example in certain embodiments,a film fixation system for film fixation at an anatomical site caninclude 1) a film and 2) a film fixation element where the fixationelement securely affixes the film to the anatomical site, preferablysecurely affixes the film to a medical device at the anatomical site orto a tissue such as a bone or tendon at the anatomical site. Accordingto one embodiment, the fixation element is a screw, pin, wire, suture,staple, glue, or combinations thereof. In addition, the polymer film(with or without an adhesive layer) may be wrapped around the medicaldevice one or more times. It should be appreciated that in certainembodiments as described above, the adhesive layer of the film canfunction as the film fixation element. According to still anotherembodiment, the system for film fixation can be further combined with amedical device to provide a system for treatment, for example a systemfor fracture fixation including 1) an orthopedic medical device and 2) afilm fixation system including a film and a film fixation element.

The different possibilities for affixing the polymer film to the medicaldevice or tissue provides a user with flexibility. In certain of theseembodiments, the user can size and shape the polymer as desired orneeded and can cover all or part of the medical device surface or tissuewith the polymer film. For example, one could selectively affix thepolymer film to only a bone-facing surface of the implant.

Referring to FIGS. 2 and 11A-11J, after creating the film 10, the film10 can be formed into an active biocompatible implant cover 25configured for placement onto or over a surface of a medical implant.The biocompatible implant cover 25 can be referred to as active in thatit includes one or more active agents of the type described herein,alone or in combination, such that when implanted, the activebiocompatible implant cover 25 delivers the one or more active agents.The medical implant can be a bone implant, such as an intramedullarynail or a bone plate, or any alternative medical implant (such as animplant for use in orthopedic and/or musculoskeletal repair), the film10 is shaped and fashioned to generally correspond to conform to theshape of at least a portion or substantially all of the bone plate 12.In some embodiments, at least one film 10 is shaped and fashioned into acover 25 that can be configured as a sleeve 31 (see FIGS. 11A-I 1J and17A-26H) that is configured to receive at least a portion or an entiretyof the bone plate 12, or a strip that can be adhesively attached to oneor more surfaces of the bone plate 12. It should be further appreciatedthat one or more surfaces of the sleeve 31 can have adhesive propertiesso as to adhesively attach to one or more surfaces of the bone plate 12.

Referring to FIGS. 11A-11J and 17A-26H in general, the sleeve 31includes at least one film 10 that defines a first sleeve portion 31 aand a second sleeve portion 31 b that is spaced from the first sleeveportion 31 a along the transverse direction T. The apertures 14 of thefirst sleeve portion 31 a can be aligned with the apertures 14 of thesecond sleeve portion 31 b, or at least one or more up to all of theapertures 14 of the first sleeve portion 31 a can be offset with respectto all others of the apertures of the second sleeve portion 31 b alongeither or both of the lateral and longitudinal directions. The firstsleeve portion 31 a defines an inner surface 35 a and an outer surface37 a opposite the inner surface 35 a. Similarly, the second sleeveportion 31 b defines an inner surface 35 b and an outer surface 37 bopposite the inner surface 35 b. The inner surfaces 35 a and 35 b faceeach other, and the outer surfaces 37 a and 37 b face opposite eachother.

Either or both of the inner surfaces 35 a and 35 b can be defined by oneof the first surface 10 a or the second surface 10 b, and either or bothof the outer surfaces 37 a and 37 b can be defined by the other one ofthe first surface 10 a or the second surface 10 b. It should thus beappreciated that the meniscuses 17 (see, e.g., FIG. 1A) can be disposedat either the inner surface 35 a or the outer surface 37 a, and canfurther be disposed at the inner surface 35 b or the outer surface 37 b.In one embodiment, the first and second sleeve portions 31 a and 31 bare monolithic with each other, such that the meniscuses 17 are disposedon either both inner 35 a and 35 b or both outer surfaces 37 a and 37 b.Because the at least one film 10 of the sleeve 31 is flexible, thesleeve 31 can be iterated between a first closed configuration wherebythe first and second sleeve portions 31 a and 31 b, and in particularthe inner surfaces 35 a and 35 b, are immediately adjacent each otheralong the transverse direction T such that the sleeve 31 does not definean opening between the first and second sleeve portions 31 a and 31 b,and a second open configuration whereby the sleeve 31 defines an opening33 between the first and second sleeve portions 31 a and 31 b, and inparticular between the inner surfaces 35 a and 35 b. Thus, the innersurfaces 35 a and 35 b can be referred to as implant facing, or boneplate facing, surfaces.

The opening 33 defined between the first and second sleeve portions 31 aand 31 b. The opening 33 can be sized so as to define a height in thetransverse direction T and a width in the lateral direction A that is atleast equal to, and can be greater than, the respective height and widthof the bone plate 12 that is received in the opening 33. The opening 33can have a length along the longitudinal direction L that can be equalto, less than, or greater than, the length of the bone plate 12 suchthat the opening 33 is sized to receive at least a portion up to all ofthe bone plate 12. Accordingly, each of the sleeve portions 31 a and 31b is configured to cover at least a portion, and up to all, of at leastone surface of the bone plate 12.

The sleeve 31 can be configured in any manner as desired. For instance,the film 10 can be created in any manner described herein, and shaped soas to define a shaped film that can correspond to the shape of apreselected bone plate shape that is to be received in the resultingsleeve 31. After the film 10 has been molded, material of the resultingfilm 10 can be removed so as to define a first shaped film that cancorrespond to the shape of a preselected bone plate shape. A secondshaped film substantially identical to the first shaped film can becreated from the same film 10 that defined the first shaped film, orfrom a separate film 10. For instance, material can be removed from therespective film 10 so as to define the second shaped film. The first andsecond shaped films 10 can be positioned adjacent each other such thattheir respective outer peripheries are aligned along the transversedirection T. At least a portion of the outer peripheries of the firstand second films can be attached to each other by any one of theattachment methods of the type described herein so as to define aclosure 16, such as an attachment or an alternatively configuredclosure, such that the first shaped film defines the first sleeveportion 31 a and the second shaped film defines the second sleeveportion 31 b.

The closure 16 can extend about a portion of the periphery 39 of thesleeve 31. For instance, the sleeve 31 can define a front end 39 a and aproximal portion 43 a that is disposed proximate to the front end 39 a,and a rear end that is spaced from the front end 39 b along at least thelongitudinal direction L (which includes embodiments in which at least aportion of the front and rear ends 39 a and 39 b can further be spacedfrom each other along the lateral direction A) and defines a distal end43 b disposed proximate to the rear end 39 b. The sleeve 31 can furtherdefine first and second sides 39 c and 39 d, respectively, that arespaced from each other along at least the lateral direction A (whichincludes embodiments in which at least a portion of the first and secondsides 39 c and 39 d can further be spaced from each other along thelongitudinal direction L). The first and second sides 39 c and 39 dextend between the front and rear ends 39 a and 39 b, for instance fromthe front end 39 a to the rear end 39 b. The ends 39 a and 39 b incombination with the sides 39 c and 39 d can define the outer periphery39 of the sleeve 31. The closure 16 can extend about a portion of theouter periphery 39 so as to define at least one opening 41 at the outerperiphery 39 between the first sleeve portion 31 a and the second sleeveportion 31 b. For instance, the closure 16 can extend along a portion oran entirety of the rear end 39 b, a portion or an entirety of one orboth of the first and second sides 39 c and 39 d, and a portion or anentirety of the front end 39 a, both alone or in combination. Forinstance, in one embodiment, the first and second sides 39 c and 39 dand the rear end 39 b are attached, such that the sleeve 31 defines theopening 41 at the front end 39 a. Alternatively or additionally, thesleeve 31 can define a second open end at the rear end 39 b.Alternatively or additionally, the sleeve can define a third or fourthopening at one or both of the sides 39 c and 39 d, respectively. One ormore of the first, second, third, and fourth openings can be continuouswith each other.

When the sleeve 31 is in the open configuration, the opening 41 can bedimensioned such that the bone plate 12 can be inserted into, andremoved from if desired, the opening 41 and into and out of the opening33. Alternatively, the bone plate 12 can be placed between the first andsecond sleeve portions 31 a and 31 b, and a substantial entirety of theperiphery of the sleeve 31 can define the closure 16, such that the boneplate 12 is disposed in the opening 33 and substantially encapsulated bythe sleeve so as to be non-removable from the film, meaning that thesleeve 31 does not define an opening at the outer periphery 39 that issized sufficiently for the bone plate 12 to be removed from the sleeve31 without breaching either of the sleeve portions 31 a and 31 b or theclosure 16. It should be appreciated that when the bone plate 12 isdisposed in the opening, the first and second sleeve portions 31 a and31 b cover at least a portion of respective opposed surfaces of the boneplate 12.

In accordance with one embodiment, either or both of the outer periphery39 of the sleeve 31 and an outer periphery of the opening 33, such ascan be defined by the inner periphery of the closure 16 or otherclosure, can extend parallel to an outer periphery of the bone plate 12,such that the sleeve 31 can define a sheath. Thus, it should beappreciated that the closure has an inner boundary that defines an outerperiphery of the opening 33, and at least a portion up to all of theinner boundary can be parallel to the outer periphery 39 of the sleeve31. It should be appreciated that the at least one film 10 can be shapedin any suitable manner as desired so as to define the sleeve 31. Forinstance, as described, two shaped films can be adjoined to define thefirst and second portions of the sleeve 31 a and 31 b. The first andsecond shaped films can be produced by cutting a respective one or twomolded films 10. Alternatively, the cavity of the mold can be shaped soas to define the outer periphery 39 of the sleeve 31, and the as-moldedfilm can be removed from the mold and thus define the shaped film.Alternatively still, the films 10 can be attached in the mannerdescribed herein such that the inner periphery of the closure 16 issized and shaped such that the resulting opening 33 is sized to receivea plurality of differently shaped bone plates 12 and the inner peripheryof the closure 16 does not extend parallel to the outer periphery of thebone plate 12.

As described above, the sleeve 31 can include a closure 16, such as anattachment or alternatively configured closure as desired. For instance,a single film 10, which can be shaped as desired, can be folded aboutitself along a fold, such that the film defines the first and secondportions 31 a and 31 b of the sleeve 31 that are separated from eachother by the fold. Thus, the fold can be said to define a closure at aportion of the outer periphery 39 of the sleeve 31. The fold can bedisposed, for instance at a midline of the film 10, such that the film10 defines two symmetrical regions separated from each other by thefold. The fold can define a fold line, or the film 10 may be shaped intoa cylinder and the two opposed edges of the film that are opposite thefold can, in combination, define one of the sides of the sleeve 31.Resulting open portions of the outer periphery 39 of the sleeve 31 canbe left open as desired, or closed, for instance attached in the mannerdisclosed above. Thus, the folded film 10 can be at least partiallyattached to itself. For instance, the free ends of the film 10 can beattached to each other so as to define an attachment at one of the firstand second sides 31 c and 31 d of the sleeve 31, and the fold can definethe other of the first and second sides 31 c and 31 d. Thus, the sleeve31 can include a closure 16 at both the first and second sides 31 c and31 d. In one embodiment, the second surface 10 b overlaps the firstsurface 10 a at the opposed edges of the film 10 such that the firstsurface 10 a defines the inner sleeve surfaces 35 a and 35 b at theopposed edges of the film 10 so as to define at a least a region of theclosure 16 when the opposed edges of the film 10 are attached to eachother. Alternatively, the first surface 10 a overlaps the second surface10 b at the opposed edges of the film 10 such that the second surface 10a defines the inner sleeve surfaces 35 a and 35 b at the opposed edgesof the film 10 so as to define a least a region of the closure 16 whenthe opposed edges of the film 10 are attached to each other. The twosymmetrical regions of the film 10 can be shaped so as to correspond tothe preselected bone plate shape, for instance by removing material ofthe film 10 or by contouring the mold cavity in the manner describedabove.

It should be appreciated that in some embodiments, the closure 16, suchas the attachment, can be visible through at least one of the first andsecond sleeve portions 31 a and 31 b as illustrated in FIGS. 11A, 11B,11D, and 11E, or can be hidden by the first and second sleeve portions31 a and 31 b, for instance as illustrated in FIGS. 11C and 11F-11J.Accordingly, those embodiments in which the closure 16, such as theattachment, is visible can be constructed such that the closure 16, suchas the attachment, is hidden, and thus the outer periphery can beillustrated as shown in FIGS. 11C and 11F-11J. Conversely, thoseembodiments in which the closure 16, such as the attachment, is hiddencan be constructed such that the closure, such as the attachment, isvisible, and thus the outer periphery 39 can be illustrated as shown inFIGS. 11A, 11B, 11D, and 11E.

Referring now to FIGS. 11A-11J and FIGS. 17A-26H, the sleeve 31 candefine any suitable size and shape as desired. For instance, the sleeve31 can be constructed as any suitable sized and shaped sheath as desiredthat is configured to form fit the bone that is to be received in therespective opening (such that the inner periphery of the closure 16 issubstantially parallel to the outer periphery of the bone plate 12). Asillustrated in FIGS. 11A-11C and 17A-19H, the sleeve 31 can define across-sectional dimension at the proximal portion 43 a along the lateraldirection A that is greater than the cross-sectional dimension of thesleeve 31 at the distal portion 43 b along the lateral direction A. Forinstance, at least one of the sides 31 c and 31 d can define a flaredregion 45 that extends laterally out from an adjacent region of therespective side as it extends along a direction from the rear end 39 btoward the front end 39 a, and thus is flared along the lateraldirection A away from the opposed side with respect to the adjacentregion of the respective side as it extends along a direction from therear end 39 b toward the front end 39 a. The flared region 45 of one ofthe sides 31 c and 31 d can extend laterally out further or an equalamount (see FIGS. 11H, 11I and 24A-25H), with respect to the flaredregion 45 of the opposed side. Further, the flared region 45 of one ofthe sides 31 c and 31 d can define the same shape (see FIGS. 11H, 11Iand 24A-25H) or a different shape with respect to the flared region 45of the opposed side. In accordance with the illustrated embodiment atFIGS. 11A and 17A-H, the flared region 45 at the second side 39 dextends laterally out further than the flared region at the first side39 c. Thus, it should be appreciated that a portion of the front end 39a is offset with respect to the rear end 39 b along the lateraldirection. Either or both of the front end 39 a and the rear end 39 bcan be curved (e.g., convex as illustrated or concave as desired) orstraight as desired in all embodiments, unless otherwise indicated. Inaccordance with the illustrated embodiment at FIGS. 11B, 11C, 18A-18H,and 19A-19H, the second side 39 d includes the flared region 45 and thefirst side 39 c is linear from the front end 39 a to the rear end 39 b.Referring now to FIGS. 11D-11G and 20A-23H, both the first and secondsides 39 c and 39 d can extend linearly and parallel to each other fromthe front end 39 a to the rear end 39 b. The rear end 39 b can be curvedor straight as desired. The length of the sleeve 31 can be any dimensionas desired from the front end 39 a to the rear end 39 b along thelongitudinal direction L. Similarly, the width of the sleeve 31 can beany dimension as desired from the first side 39 c to the second side 39d along the lateral direction A. Referring to FIGS. 11J and 26A-H, theflared region 45 at one of the sides 39 c and 39 d can extend laterallyinward toward the other one of the sides 39 c and 39 d, and the flaredregion 45 at the other one of the sides 39 can extend laterally outward.For instance, as illustrated, the proximal end 43 a of the first side 39c can extend laterally inward toward the second side along a directionfrom the rear end 39 b toward the front end 39 a. The proximal end 43 aof the second side 39 d can extend laterally outward away from the firstside 39 c along a direction from the rear end 39 b toward the front end39 a. Moreover, the flared region 45 can extend to a location spacedfrom the front end 39 a along a direction from the front end 39 a towardthe rear end 39 b, such that a length of the proximal portion 43 a thatextends between the flared region 43 and the front end 39 a extendsparallel to an adjacent region of the respective side, such as side 39d, that is disposed adjacent the flared region 45.

As described above, the active biocompatible implant cover 25 can beconfigured as a sleeve, such as any sized or shaped sleeve 31 asdesired, which can define a sheath, or the implant cover 25 can bealternatively configured as desired. For instance, the implant cover 25can be configured as one or more strips of the film 10 that areconfigured to overlay at least a portion of one or more surfaces of thebone plate 12. The strips can be shaped as described above such that theouter periphery of the strips is substantially aligned with, or parallelto, the outer periphery of the bone plate 12, or can be sized greaterthan the bone plate 12 or less than the bone plate 12. Thus, the stripscan define any size and shape as desired, for instance the shapes asillustrated in FIGS. 11A-11J and FIGS. 17A-26H with respect to thesleeve 31, or any alternative shape as desired. The strips can furtherbe sized greater than the sizes of the sleeves 31 illustrated in FIGS.11A-11J and FIGS. 17A-26H, or less than the sizes of the sleeves 31 asillustrated in FIGS. 11A-11J and FIGS. 17A-26H. Thus, one or more of thestrips can be placed along a portion up to all of the bone facingsurface of the bone plate 12, a portion up to all of the outer surfaceof the bone plate 12 that is opposite the bone facing surface, or both.The strip can define an inner surface that faces the bone plate 12, andan outer surface that faces away from the bone plate 12. The innersurface of the strip can be defined by the first surface 10 a or thesecond surface 10 b. Conversely, the outer surface of the strip can bedefined by the first surface 10 a or the second surface 10 b.

In one embodiment, the strips can be sized so as to wrap around the boneplate 12, for instance at least one-half of a revolution about the boneplate 12 such that the strip overlays at least a portion of the bonefacing and outer surfaces of the bone plate 12. The strip can be wrappedaround the bone plate 12, as many full revolutions as desired until thestrip overlays a sufficient area of one or both of the bone facing andouter surfaces of the bone plate 12 as desired. The strip can bedimensioned as desired, for instance by removing material from theas-molded film 10, or by contouring the mold cavity to define a desiredsize and shape of the strip.

As described herein, at least a portion of film 10 or films 10 can beattached to each other by attachment methods to define a closure 16,such as an attachment. In certain embodiments, the attachment can bedefined by attachment components, such as a seam, glue, sutures,staples, pins, wires, screws, heat, ultraviolet light, or a combinationthereof that attach a first region of film to a second region of filmthat overlaps the first region of film, for instance along thetransverse direction T. Accordingly, two regions of the same film or twoseparate films may be attached to form a sleeve 31. For example, firstand second films 10 can be positioned adjacent each other such that afirst region of film, which can be defined by the first film 10,overlaps with a second region of film, which can be defined by thesecond film 10. The first and second regions of film can overlap alongany direction as desired, such as the transverse direction T. Theoverlapping first and second regions of film can be attached to eachother with one of the attachment components. Alternatively, a singlefilm 10 can be formed into a sleeve by folding the film 10 so as to atleast partially define a closure 16, and contouring the single film suchthat free ends overlap. Thus, the free ends of the single film 10 candefine the first and second overlapping regions of film. The overlappingfirst and second regions of film, whether monolithic with each other anddefined by the same film 10, or defined by different films 10, can beattached to each other by applying any of the above described attachmentcomponents to one or both of the first and second overlapping regions offilm so as to at least partially define a closure 16. For instance, aglue can be applied along one or both surfaces of the overlapping firstand second regions of film that face each other, and the surfaces can bebrought against each other and/or the glue. In another embodiment, theattachment can be defined by applying heat and/or pressure to the firstand second overlapping regions until the regions of film begin to soften(or melt) and integrate with one another, and subsequently allowing theportions to re-solidify. In addition, multi-film sleeves and strips maybe prepared by attaching two separate films that are immediatelyadjacent each other, for instance in the transverse direction T.

In addition to sleeves 31, film 10 may be used, in some embodiments, forother medical applications such as hernia repair mesh, adhesion barrier,soft tissue augmentation, filtration membranes, drug delivery membranes,bone graft containment (e.g., for maintaining bone graft in place forexample in a spinal fusion procedure, or segmental defect grafting in along bone), or wound care products such as bandages.

The polymer film may be used at any surgical site susceptible tomicrobial infection. Such methods can be used with any polymer filmembodiment and/or combination of embodiments disclosed herein.Typically, the methods comprise identifying a surgical site in need ofmicrobial inhibition and contacting the surgical site with a polymerfilm comprising an active agent. The methods may also involveidentifying a zone at a surgical site or on a medical implant needingmicrobial inhibition (zone of inhibition), contacting the medicalimplant with the polymer film, and implanting the medical implant at thesurgical site. In certain embodiments, the polymer film is used inconjunction with medical implants comprised of material that issusceptible to bacterial colonization, for example, implants comprisingmetal.

The polymer film may be used in conjunction with metal bone plates to beimplanted at fracture sites in the extremities, particularly the lowerextremities, such as fractures associated with the femur, fibula, andtibia. Following implantation, the bacterial growth at the surgical sitemay be monitored to determine the effectiveness of the treatment.

The implant may be contacted with the film in any manner as describedherein. For example, the film may be in the form of an implant coverconfigured for placement onto or over a surface of a medical implant. Inthe case of a sleeve, the polymer film is slipped over at least aportion of the implant. As described herein, the sleeve can include atleast one open end, and in certain embodiments two open ends.Alternatively, the polymer film may be adhered or affixed to the implantvia adhesive or fixation devices such as sutures, screws, or other typesof fasteners. Typically, a doctor will select an implant with the propercontour, such as a bone plate, to treat the bone fracture at issue. Inthe case of percutaneous procedures, and before implant fixation, acavity within the soft tissue may be prepared to reduce the stresses onthe polymer film during implant insertion.

The contacting of the polymer film and implant is typically done at ornear the time of surgery, i.e., intraoperatively, such that the surgeoncan match the polymer film with the medical implant to be contactedbased on size and shape and the drug requirements for the subjectpatient. If the implant is in the form of a sleeve, the sleeve may beapplied by opening it and inserting the implant, such as a bone plate,until the anatomic portion of the plate is seated in the sleeve. Thesleeve may cover the entire implant or a portion of the implant. Forexample, the sleeve may be trimmed and/or folded to conform to theimplant as desired. Prior to instrumentation attachment orscrew/fastener insertion of the medical implant at the surgical site,the polymer film may be pierced through the holes in the implant thatwill be used during final implant fixation. This will provide anunimpeded path for the screw/fastener through the polymer film. Theimplant may then be affixed using standard surgical procedures.

Total drug dosing of the polymer film is a function of the size of theimplant as well as surgical need. In one embodiment, the polymer filmcontains approximately 0.6 mg of gentamicin sulfate per squarecentimeter of surface area. The total dose of drug delivered depends onthe size of the polymer film and the implant it is designed to contact.In certain embodiments, a surgeon will determine the amount ofantibiotic that is needed at a surgical site of a particular patient.The polymer film may then be manipulated to meet the delivery need. Forexample, if the patient requires more antibiotic than is available in asingle polymer film, multiple polymer films may be used and/or longer orotherwise larger films may be selected. To the extent the polymer filmis in the form of a sleeve, an implant may be fitted with multiplesleeves. If the patient requires less antibiotic, the polymer film maybe reduced by, e.g., cutting or trimming. As indicated herein, thesurgeon may determine an appropriate zone of inhibition that willprevent bacterial colonization on an implant even if the polymer film isnot contacting the entire surface area of the implant, such that cuttingor trimming the polymer film may reduce the overall drug load, but notreduce the effectiveness of the anti-microbial treatment.

In one embodiment, there is an initial release of 20% of the drugcontent in the film within one hour of implantation. This is followed bya sustained release of the remaining drug content for approximately 7 to10 days. The polymer film itself is completely degraded by hydrolysisand absorbed by the body within 60-90 days of implantation.

In the case of gentamicin, gentamicin-related nephrotoxicity is relatedto duration of treatment, and is typically transient although fullfunctional recovery may not occur for several months after therapystops. Nephrotoxicity is also related to plasma gentamicin levels, withrecommended trough levels not to exceed 2.0 μg/ml. Peak plasmagentamicin levels released from the polymer film have been found to bewell below this level in sheep studies, including in the range of 0.1μg/ml. Local administration of gentamicin may be particularlyadvantageous as compared to systemic antibiotic treatments. According toone embodiment, local delivery of gentamicin provides a higherconcentration of antibiotic at a surgical site than a comparablestandard of care amount of systemic antibiotic treatment, thuspermitting a higher potential for eliminating bacterial growth at thesite. According to another embodiment, local delivery of gentamicinprovides a lower plasma concentration than a comparable standard of careamount of systemic antibiotic treatment, thus potentially reducingpotential adverse effects, for example nephrotoxicity, that can resultfrom systemic antibiotic treatments. Thus, local delivery provides anopportunity to deliver higher concentration of antibiotics with anoverall smaller quantity than systemic treatments.

In one embodiment, the method of inhibiting microbial infection at asurgical site comprises contacting a medical implant with a polymer filmof the present disclosure at or near the time of surgery, wherein thefilm comprises a drug component having a particle size of 10 microns orless, and implanting the medical implant at the surgical site. Asdescribed herein, with respect to bacteria, the polymer film is able toproduce a 5 to 7-log reduction of colony forming units.

In more particular embodiments of the method, the polymer film is in theform of a sleeve and comprises a bioresorbable film comprising acopolymer of glycolide, trimethylene carbonate, lactide andcaprolactone, the active agent is gentamicin sulfate, and the surgicalsite is a bone fracture site of the lower extremities, such as thetibia.

Example 1

Film preparation: Films were produced from a copolymer of approximately:70% glycolic acid, 17% caprolactone, 5% lactic acid and 8% trimethylenecarbonate (US Surgical, North Haven, Conn.). This copolymer wasdissolved in dimethyl sulfoxide (DMSO) at a concentration of 20% byweight, and either cast as a thin film onto a 20 cm×20 cm glass plate,or mixed with 5% or 10% gentamicin sulfate and then cast. Cast filmswere dried in air at 60° C. for a minimum of 12 hours to remove solvent,then removed from the glass plate and stored under vacuum for furthertesting. Finished films had a thickness of 0.06±0.01 mm.

Tensile testing: 10 mm×80 mm strips cut from the cast films were testedin tension to failure on an Instron test stand (model 3342) at 20mm/sec, dry and at room temperature, per ASTM D882. Initial yield stressof the films tested at t=0 are shown in FIG. 12 and the elongation ofthe films at yield are shown in FIG. 13. Incorporation of gentamicinsulfate into the films results in a minor decrease in tensile strengthand elasticity.

Drug release testing: 19 mm diameter disk samples cut from cast films(5% & 10% gentamicin) were placed in PBS at 37° C. Concentration ofgentamicin in solution was measured at 15 min, 30 min, 1 hr, 2 hr, 4 hr,6 hr, 1 d, 2 d, 4 d, 7 d and weekly up to 12 weeks, using fluorescencepolarization immunoassay technique (TDxFLx, Abbott Laboratories).Results are shown in FIG. 14.

In-vitro degradation: 19 mm diameter disk samples cut from cast films(plain, 5% gentamicin, 10% gentamicin) were weighed and placed intovials containing phosphate buffered saline solution (PBS) at 37° C. for1 d, 4 d, 7 d and weekly up to 10 weeks. Fresh PBS was changed weeklyand the pH was monitored. At test times, the samples were removed fromthe solution, freeze dried, and weighed. The inherent viscosity of eachsample was also measured by dilute solution viscosity (Cannon-Ubbelhodesemi micro viscometer, in HFIP at 25° C.). In-vitro degradation of allpolymer films proceeded at a similar rate, regardless of the level ofincorporated gentamicin, as shown in FIG. 15. Molecular weight of thepolymer as measured by inherent viscosity dropped rapidly within thefirst 7 days in-vitro, then at a slower rate, as shown in FIG. 16.

Example 2

In one exemplary embodiment, implants were tested by implantation insheep. The implants were metal plates with tubular, thin (0.05-0.08 mm),transparent polymer sleeves carefully slipped over the metal plates justbefore they were surgically inserted and attached to the bone. Thesleeves had a tight fit, covered the metal plates completely over theentire length, although they were open at both ends of the plates. Thesleeves were comprised of a synthetic copolyester (glycolide,caprolactone, trimethylenecarbonate, lactide) with aperture holes of 1.5mm diameter equally spaced throughout. One group of sleeves containedtriclosan (2,4,4□-trichloro-2□-hydroxydiphenyl ether) at a concentrationof 1%, one group of sleeves contained gentamicin at a concentration of10%, and one group of sleeves contained a combination of both triclosan(1%) and gentamicin (10%). The concentration of gentamicin and Triclosanwere chosen based on in vitro testing to determine the therapeuticwindow for each compound.

The hydrophobic triclosan was in complete solution within the polymer,in contrast to the hydrophilic gentamicin, which remained suspended as10-20 μm small particles. In vitro testing has shown that due to itspoor water solubility, triclosan is released from these films onlyslowly over a to 3 weeks period, with minimal initial burst release.

Approximately 50% of the more water soluble gentamicin which is exposedto the surface of the sleeves was released into the adjacent tissuewithin 24 hours after insertion. The remaining gentamicin encapsulatedin the depth of the polymer dissolves more slowly and was released overa 2 to 3 week period after implantation. The polymer was designed todegrade through hydrolysis within 60 days after surgery.

The sleeves with or without antimicrobial agents were provenbiocompatible, with minimal effect on soft tissue and bone healing andnot corrosive to the metallic implants. Additional details of theexperiment can be found in Vet Surg. 2012 Jan. 12. Biodegradable Sleevesfor Metal Implants to Prevent Implant-Associated Infection: AnExperimental In Vivo Study in Sheep. von Plocki S C, Armbruster D, KleinK, Kampf K, Zlinszky K, Hilbe M, Kronen P, Gruskin E, von Rechenberg B.,which is hereby incorporated by reference in its entirety.

Example 3

In one exemplary embodiment, film 10 is manufactured by the followingmethod:

Determination of Gentamicin Moisture Content:

The moisture content of gentamicin sulfate powder is measured by a losson drying method. Approximately 0.5 grams of gentamicin is weighed in aglass jar, then heated under vacuum to 110° C. for 3 hours and weighed asecond time. The weight loss is recorded as the moisture content, whichis used to calculate the percent moisture.

Solution Mixing:

14.69 grams of gentamicin sulfate powder is weighed, compensating forthe percent moisture content as calculated above. This is mixed into 400g of DMSO solvent in a 1 L vessel, using a paddle mixer. The mixture isstirred for 30 minutes until the gentamicin is uniformly distributed.100 g of a copolymer containing glycolic acid, caprolactone, lacticacid, and trimethylene carbonate monomers is added to the suspension,and the mixing vessel is heated to 65° C. Mixing is continued for 2hours until the polymer is completely dissolved into the solution, thenthe solution temperature is reduced to 55° C.

Film Casting & Solvent Drying:

A casting mold and drawing blade made from high density polyethylene areused to cast thin perforated films from the polymer solution. Thecasting mold and drawing blade are pre-cleaned using an alkalinedetergent solution and loaded into an automated CNC casting fixture. 15ml of the polymer solution are drawn up in a polypropylene syringe,which is loaded into the casting fixture. The casting fixtureautomatically dispenses the solution onto the casting mold, and drawsthe blade across the surface of the mold. The mold filled with polymersolution is placed into a solvent drying oven at 85° C. forapproximately 90 minutes to dry the film. The molds are removed from thedrying oven and the films are peeled from the molds within 2 minutes.

Sleeve Sealing:

An impulse heat sealing press with specially shaped dies is used to sealand cut the cast film into the shape of a sleeve. Two cast films areplaced into the press, and the press is closed with a pressure of 80 psiand heated to 200° C. for 4 seconds. The sleeves are removed from theexcess film material and cut to the appropriate length. Sealed sleevescan be dried under vacuum at 50° C. and sealed in moisture barrierpackaging to prevent degradation of the bioresorbable polymer.

Example 4

In vitro studies have been conducted to evaluate the effectiveness of agentamicin containing resorbable polymer film to prevent colonization ofmetal implants by common bacterial pathogens. Colonization assays usingagar to simulate soft tissue coverage of stainless steel and titaniumfracture fixation plates have shown that the film is effective inpreventing bacterial colonization of the metallic implants byStaphylococcus aureus, Staphylococcus epidermidis, Pseudomonasaeruginosa and Enterobacter cloacae. These data represent at least a 5to 6-log reduction in bacterial counts compared to metallic implantswith no film (control).

In time to kill assays, stainless steel plates were inoculated withbacteria. The gentamicin sulfate containing film was then placed on theplate and the number of surviving bacteria were measured at differenttime points. Time to kill data for target bacteria are shown below. Thegentamicin film was effective to produce a 5 to 7-log reduction inbacterial colonization—measured as “colony forming units” (CFU)—by allGram positive (shown in blue: Staphylococcus aureus (MSSA),Staphylococcus aureus (MRSA), Staphylococcus aureus (MDR) andStaphylococcus epidermidis) and Gram negative (shown in green:Pseudomonas aeruginosa, Enterobacter cloacae, and Acinetobacterbaumannii) target bacteria, except for a multi-drug resistant strain ofS. aureus, and the anaerobe P. acnes, both of which are typicallygentamicin resistant. FIG. 27 illustrates the effectiveness of thegentamicin sulfate containing film in preventing colonization ofstainless steel in vitro (various bacteria per ISO 22916)

Example 5

The objective was to measure the zone of inhibition of a gentamicinfilm. Testing was performed with 4 different species of bacteria.

Samples

6 mm punches of the gentamicin film (0.1%, 0.5%, 1.0%, 5.0%, and 13%gentamicin sulfate, anhydrous) (the 13% gentamicin film was testedseparately from the other gentamicin films and the data was separatelycollected and produced)

Controls

blank filter disk w/ 120 ug Gentamicin in 30 ul dPBS; blank filter diskin 30 ul dPBS

Bacteria

S. aureus ATCC 25923; S. epidermidis ATCC 12228; Pseudomonas aeruginosaATCC 10145; Enterobacter cloacae ATCC 29941

Materials & Instrument

Glass culture tubes (VWR #: 89001-480); Blank Disks, 6.35 mm diameter(VWR#: 90002-114); 6 mm Disposable Biopsy Punches (VWR#: 21909-144);Mueller Hinton agar dishes (VWR #: 100219-188); 0.5 McFarland turbiditystandard (VWR #: 29447-318); dPBS (VWR #: 12001-664); Cotton swabs;Incubator; Thermometer; Bacterial hood

Experimental Method

Add colonies from an agar dish which was incubated o/n at 36° C. todPBS.

Adjust turbidity with dPBS to 0.5 McFarland Standard equivalent.

Within 15 minutes of adjusting turbidity, dip a sterile cotton swab intothe dPBS. Swirl the swab in this tube and when removing the swab, pressit into the side of the tube above the liquid.

Inoculate Mueller-Hinton agar plates by streaking once down the middleof the plate. Then streak the swab all over the plate; rotate 2×'s˜60°each time. After streaking the entire plate, streak the swab around therim of the plate.

Place filter disks/punches onto the dish.

Place in the 36° C. incubator within 15 minutes inoculating dish.

Incubate 16-18 hours.

Measure ZOI in millimeters using slide caliper (ZOI was measured alinear distance measured through the center point of the disk). FIG. 28illustrates the minimum effective concentration and measured ZOI.

Avg. ZOI (mm) S. P. S. aureus E. cloacae epidermidis aeruginosa Blank0.00 0.00 0.00 0.00 120 ug gentamicin 30.5 22.4 34.9 26.7 5% gentamicin21.2 17.4 27.2 12.9 1% gentamicin 15.1 12.3 19.8 0.0 0.5% gentamicin13.4 10.0 15.7 0.0 0.1% gentamicin 0.0 0.0 6.7 0.0

Avg. ZOI (mm) S. P. S. aureus E. cloacae epidermidis aeruginosa Blank0.00 0.00 0.00 0.00 120 ug gentamicin 28.73 25.27 31.37 24.90 13%gentamicin 25.80 22.40 29.87 20.33

Example 6

In order to evaluate the effectiveness of a gentamicin sulfatecontaining polymer film to prevent bacterial colonization, stainlesssteel fracture fixation plates were covered with gentamicin sulfatecontaining polymer films in the form of sleeves or sleeves that were tooshort to cover the full plate, i.e., only half of the plate (5.5 cm ofthe 11 cm long plate) was covered. These plates were inoculated withbacteria and evaluated for antimicrobial activity in a 3-dimensionalagar assay which simulates soft tissue coverage Four common pathogens(P. aeruginosa, S. aureus, E. cloacae, and S. epidermidis) wereevaluated, and the gentamicin sulfate containing polymer film (13% byweight gentamicin) effectively prevented colonization of the steelplates, even those surfaces of the plates not covered by the polymerfilm (5 to 6 log reduction in CFU relative to controls). FIG. 29illustrates the measured zone of inhibition for the various bacteria.

It will be appreciated by those skilled in the art that changes could bemade to the exemplary embodiments shown and described above withoutdeparting from the broad inventive concept thereof. It is understood,therefore, that this disclosure is not limited to the exemplaryembodiments shown and described, but it is intended to covermodifications within the spirit and scope of the present disclosure asdefined by the claims. For example, specific features of the exemplaryembodiments may or may not be part of the claimed invention and featuresof the disclosed embodiments may be combined. Unless specifically setforth herein, the terms “a”. “an” and “the” are not limited to oneelement but instead should be read as meaning “at least one”.

It is to be understood that at least some of the figures anddescriptions of the invention have been simplified to focus on elementsthat are relevant for a clear understanding of the disclosure, whileeliminating, for purposes of clarity, other elements that those ofordinary skill in the art will appreciate may also comprise a portion ofthe invention. However, because such elements are well known in the art,and because they do not necessarily facilitate a better understanding ofthe invention, a description of such elements is not provided herein.

Further, to the extent that the method does not rely on the particularorder of steps set forth herein, the particular order of the stepsshould not be construed as limitation on the claims. Further, it shouldbe appreciated that method steps of all embodiments can be incorporatedinto the method steps of any other embodiment described herein unlessotherwise indicated, and structural features of all embodiments can beincorporated into all other embodiments unless otherwise indicated. Theclaims directed to the method of the present invention should not belimited to the performance of their steps in the order written, and oneskilled in the art can readily appreciate that the steps may be variedand still remain within the spirit and scope of the present invention.

1. A flexible body comprising: a film having a first surface and anopposing second surface, the film having a plurality of aperturesextending from the first surface to the second surface and a pluralityof raised lips protruding from the first surface such that each of theplurality of apertures is surrounded by a one of the plurality of raisedlips; wherein the film comprises a plurality of layers, wherein at leastone of the plurality of layers includes a drug containing layercontaining a drug, and, wherein at least one of the plurality of layersincludes an adhesive layer.
 2. The flexible body of claim 1, wherein theadhesive layer defines one of the first surface and the second surface.3. The flexible body of claim 1, wherein at least one of the pluralityof layers includes a rate controlling layer configured to control a raterelease of the drug.
 4. The flexible body of claim 1, wherein the filmcomprises a biodegradable polymer.
 5. The flexible body of claim 4,wherein the drug is at least partially insoluble in the polymer.
 6. Theflexible body of claim 1, wherein the film further comprises one or morebiocompatible particles.
 7. The flexible body of claim 6, wherein theparticles comprise calcium-containing salt particles.
 8. The flexiblebody of claim 1, wherein the film defines a first region having theapertures and a second region devoid of the apertures.
 9. A method offorming a multi-layered film comprising: placing a first polymersolution into a mold having a plurality of protrusions extending from abottom of the mold; urging the polymer solution around each of theplurality of protrusions; placing one or more additional polymersolutions into the mold; and, solidifying the polymer solution; whereina multi-layer film having a plurality of apertures is formed.
 10. Themethod according to claim 9, wherein the step of placing one or moreadditional polymer solutions into the mold occurs prior to the step ofurging, such that urging the polymer solution includes urging the firstpolymer solution and the one or more polymer solutions.
 11. The methodaccording to claim 9, wherein the step of solidifying the polymersolution occurs both prior to and after the step of placing one or moreadditional polymer solutions into the mold.
 12. The method according toclaim 9, wherein at least one of the first polymer solution or the oneor more additional polymer solutions comprises a drug.
 13. The methodaccording to claim 9, wherein at least one of the first polymer solutionor the one or more additional polymer solutions comprises an adhesivelayer when solidified.
 14. The method according to claim 9, wherein atleast one of the first polymer solution, or the one or more additionalpolymer solutions comprises a rate controlling layer for drug releasewhen solidified.
 15. A film storage system, for the storage, packagingand/or shipment of a film comprising: the flexible body of claim 1; anda removable non-adhesive backing material placed over the adhesivelayer.
 16. A film storage system, for the storage, packaging and/orshipment of a film comprising: the flexible body of claim 1; and acollector configured to collect the film, wherein the film is separablefrom the collector.
 17. A system for orthopedic treatment comprising: anorthopedic medical device; and, a film fixation system including theflexible body of claim 1 and a film fixation element.
 18. The system fororthopedic treatment according to claim 17, wherein the orthopedicmedical device is a bone plate having a bone fixation hole.
 19. Thesystem for orthopedic treatment according to claim 18, furthercomprising a bone having a threaded shaft configured to align with thebone fixation hole.
 20. The system for orthopedic treatment according toclaim 19, wherein a diameter of the threaded shaft of the bone screw isgreater than both a cross-sectional dimension of at least two adjacentapertures and a gap between the at least two adjacent apertures suchthat the screw shaft is configured to be driven through a region of thefilm aligned with the bone fixation hole that includes more than oneaperture.